You are currently viewing a new version of our website. To view the old version click .
MDPIMDPI
Search all articles
Antioxidants
Download PDF
  • Review
  • Open Access

28 February 2024

Antioxidant Systems as Modulators of Ferroptosis: Focus on Transcription Factors

,
,
,
and
1
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
2
Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, 80137 Naples, Italy
*
Authors to whom correspondence should be addressed.
Antioxidants2024, 13(3), 298;https://doi.org/10.3390/antiox13030298
Version Notes
Order Reprints
Review Reports

Abstract

Ferroptosis is a type of programmed cell death that differs from apoptosis, autophagy, and necrosis and is related to several physio-pathological processes, including tumorigenesis, neurodegeneration, senescence, blood diseases, kidney disorders, and ischemia–reperfusion injuries. Ferroptosis is linked to iron accumulation, eliciting dysfunction of antioxidant systems, which favor the production of lipid peroxides, cell membrane damage, and ultimately, cell death. Thus, signaling pathways evoking ferroptosis are strongly associated with those protecting cells against iron excess and/or lipid-derived ROS. Here, we discuss the interaction between the metabolic pathways of ferroptosis and antioxidant systems, with a particular focus on transcription factors implicated in the regulation of ferroptosis, either as triggers of lipid peroxidation or as ferroptosis antioxidant defense pathways.

1. Introduction

In about ten years of research investigations, ferroptosis emerged as a type of cell death with a pivotal role in preventing or even facilitating the progression of many diseases (reviewed in [1,2,3]). In particular, ferroptosis is now considered a good therapeutic option to treat multiple forms of cancer and arrest tumor growth [3,4,5], as well as a causal factor in neurodegenerative disorders [6], senescence/aging [7], different blood diseases [8], and kidney- and ischemia-reperfusion injuries [9,10].
Ferroptosis has been recognized as a type of regulated, iron-dependent cell death with distinct morphologic features and molecular mechanisms differing from other forms of regulated dying pathways like apoptosis, necrosis, and autophagy-induced cell death [11]. In fact, ferroptosis is a programmed cell death that occurs when lipid peroxides accumulate because of a loss of redox homeostasis; thus, the control of lipid peroxidation represents the main regulator of ferroptosis (reviewed in [12]). Metabolic pathways triggering increased redox-reactive molecules like iron, reactive oxygen species (ROS)/reactive nitrogen species (RNS), enzymatic lipid peroxidation, and failure of endogenous antioxidant systems, mainly glutathione peroxidase 4 (GPX4)/glutathione (GSH) and coenzyme Q, can fuel ferroptosis [13]. Although the molecular mechanisms and/or metabolic pathways are still poorly understood, ferroptosis seem to be under the control of numerous transcription factors [14,15], with most of them acting as transcriptional modulators of genes implicated in lipid peroxidation and redox homeostasis, as well as iron levels.
Aim: To highlight the relationships among oxidative stress, regulatory pathways, and ferroptosis.

2. Ferroptosis as a Biological Program: Features and General Mechanisms

Beginning with the identification of apoptosis, the archetypal example of “programmed cell death,” many non-apoptotic cell death pathways, including several regulated necrotic pathways such as necroptosis, disulfidptosis, netosis, entosis, and crupoptosis, have been identified in recent years [16,17]. Although ROS and RNS are crucial in most types of cell death, it is only now becoming clear how they regulate and characterize the specific type of cell death that takes place in any given cell [18,19]. Indeed, since cellular signaling and stress response are ROS-dependent processes, it is not surprising that cell death pathways are dependent on the type and quantity of ROS/RNS production, which can function as a rheostat, enabling the activation of various cell death pathways and possibly cross-talks with other forms of cell death. As a type of non-apoptotic cell death, ferroptosis is a ROS/RNS-dependent cell death caused by the imbalance of three metabolic pillars: thiols, polyunsaturated phospholipids, and iron [20].

2.1. Role of Iron in Ferroptosis

Even though iron is necessary for cell division and survival, its accumulation combined with an increase in lipid-derived radicals and lipid peroxides may cause cell death [11]. Notably, in this context, the catalytic activity of enzymes involved in both ROS formation (lipoxygenases/LOXs, cytochrome P450/CYPs, xanthine oxidase, NADPH oxidases, mitochondrial complex I and III) and decomposition (catalase, peroxidases) relies on loosely bound iron or iron-complexes (i.e., heme or [Fe-S] clusters).
Three pools of iron are most likely representative of the iron species thought to be directly involved in ferroptosis: (i) the first one includes catalytic centers of non-heme iron proteins like LOXs utilizing iron at the active site; (ii) the storage iron pool represented by ferritin, and (iii) the major fraction represented by the redox-active, non-coordinated Fe2+ present in the cytosolic labile iron pool (LIP) that can be transported into mitochondria and utilized for heme and iron-sulfur cluster synthesis (Figure 1). Lysosomes have a very large LIP because of their role in recycling endogenous iron sources like mitochondria and ferritin and in absorbing exogenous iron. Interestingly, it has recently been reported that ferroptosis in cancer cells cannot occur unless functional lysosomes are present [21,22].
Figure 1. Role of iron in ferroptosis. An overview of the iron metabolism showing the transport mechanisms, storage, and intracellular metabolism. LIP, labile iron pool; TFR1, transferrin receptor 1; HO-1, heme oxygenase 1; POR, NADPH-cytochrome P450 reductase; LOXs, lipoxygenases. Created with BioRender.com (accessed on 31 January 2024).
In addition, intracellular iron overload can be related to dysregulated levels of several proteins involved in iron metabolism/homeostasis including transferrin, the carrier of blood ferric iron (Fe3+); transferrin receptor 1 (TFR1), which is the primary iron importer into the endosomal compartment; DMT1 (divalent metal transporter 1), which releases iron into the cytoplasmatic iron-labile pool after it has been reduced to ferrous iron Fe2+ by ferrireductases (e.g., STEAP3); ZIP14, mediating non-transferrin-bound iron import; ferritin, which stores iron; and the iron exporter ferroportin (FPN1) [23,24]. Also, autophagic degradation of ferritin (ferritinophagy), the intracellular LIP, and heme degradation by the inducible enzyme heme oxygenase 1 (HO-1) generates iron, in addition to carbon monoxide (CO) and biliverdin [25,26,27,28].
Notably, autophagy is basically a recycling pathway that can lead to cell death when it becomes disturbed [29]. An example of iron transport protein dysregulation that results in iron overload is seen in ferroptosis-sensitive Ras-mutant cells, which have elevated TFR1 and decreased ferritin levels [30]. Notably, during ferroptosis, the genes related to iron metabolism are mostly upregulated and numerous transcription factors are implicated in such control (reviewed in [31,32]).
Under physiological conditions, the ferrous iron of the LIP pool is kinetically unstable, therefore extremely reactive, and can catalyze Fenton reactions, which decompose endogenously produced hydrogen peroxide (H2O2) into highly reactive intermediate species, like hydroxyl and peroxyl radicals (HO•, HOO•) or high-valence oxo-ferryl species [33]:
Fe2+ + H2O2 → Fe3++ HO• + OH−
Fe3+ + H2O2 → Fe2++ HOO• + H+
high-valence oxo-ferryl species
Several cellular components, particularly phospholipids containing polyunsaturated fatty acid chains (PUFAs), are expected to be attacked and oxidatively damaged by the Fenton-derived ROS species, which will eventually cause lipid hydroperoxides or other hydroperoxides to become active, causing damage to membranes and other intracellular structures, thereby triggering cell death processes [34]. Additionally, it is possible that the iron centers of LOX enzymes catalyze the production of hydroperoxyl lipids (LOOH), the primary enzymatic products of lipid peroxidation, while Fe2+ from the LIP takes part in the secondary reactions of LOOH decomposition to create electrophilic products of lipid peroxidation that are oxidatively truncated [20,35,36].

2.2. Iron Accumulation and Lipid Peroxidation

The induction of ferroptosis employes specific pathways involving redox active iron and/or iron-dependent peroxidation enzymes. Iron is a fundamental cofactor for several enzymes involved in oxidation–reduction reactions due to its ability to exist in two ionic forms: ferrous (Fe2+) and ferric (Fe3+) iron. As mentioned before, in the ferroptosis context, the enzymes that catalyze lipid peroxidation are mostly heme or non-heme iron enzymes [37,38]. Consequently, iron homeostasis plays a crucial role in lipid peroxidation.
Lipids are essential components of cell membranes that maintain the structure and control the function of cells. The cellular lipid composition and the related mechanisms by which the cell imports, synthesizes, stores, and catabolizes different lipids crucially shape ferroptosis sensitivity [39,40]. In more detail, the type of unsaturated phospholipids in the cell membrane determines how cells are sensitive to ferroptosis, with PUFAs increasing the sensitivity of cells to ferroptosis whereas monounsaturated fatty acids (MUFAs) have inhibitory effects toward this cell death process [39,41].
PUFAs are a family of lipids with two or more double bounds that can be classified in omega-3 (n-3) and omega-6 (n-6) fatty acids (FAs), according to the location of the final double bond relative to the molecule’s terminal methyl terminus. The principal n-6 FAs are linoleic acid (C18:2), arachidonic acid (AA, C20:4), and its elongation product, adrenic acid (AdA, C22:4). PUFAs are important substrates for unsaturated phospholipid synthesis and also for the generation of lipid peroxides, mostly when they are incorporated into phosphatidylethanolamines (PE) [42]. The activation and esterification of AA and AdA into PE is carried out by specific enzymes, namely the acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), rendering the ACSL4/LPCAT3 axis the principal pro-ferroptotic system that under iron overload conditions can push lipid nonenzymatic autoxidation reactions or eventually increase lipoxygenase activities (as discussed later in detail).
Lipid peroxidation (Figure 2) relies on the reaction of oxygen-derived free radicals with PUFAs, resulting in lipid peroxyl radicals and hydroperoxides. The conversion of PUFAs incorporated into membrane phospholipids to peroxide PUFAs represents the initiation step to drive ferroptotic cell death [12]. Once formed, lipid peroxides can interact with ferrous iron to generate peroxyl radicals that can then abstract hydrogens from neighboring acyl chains in the lipid membrane environment to propagate the lipid peroxidation process. As mentioned before, specific PUFAs like arachidonic acid and adrenic acid are peroxidized to drive ferroptosis; however, other PUFA-containing phospholipids, including various diacyl and ether-linked phospholipids, are oxidized during ferroptosis and likely contribute to this process in a context-dependent manner [43]. In summary, the membrane phospholipid composition and therefore the endogenous pool of PUFAs dictates ferroptosis sensitivity.
Figure 2. Schematic representation of the three main pathways involved in the process of lipid peroxidation. On the left: non-enzymatic lipid peroxidation producing lipid peroxyl radicals (PL-PUFA-OO•). In the center: lipid peroxidation mediated by non-radical singlet oxygen (1O2). On the right: enzymatic lipid peroxidation cascade; the mechanism of 15-Lipoxygenase is represented. Red arrows indicate increased products. Created with BioRender.com (accessed on 31 January 2024).
In any case, although there is still much debate over whether the lipid peroxidation process is strictly controlled by enzyme activities or if it starts as uncontrollable free radical reactions, the generation of toxic lipid-derived peroxide species involves different forms of catalytically active iron. In order to better comprehend the molecular signature of ferroptosis, it is crucial to critically assess the precise role that iron plays during this process, as well as to promote the development of anti-ferroptotic strategies based on iron chelation [44].
Normally, lipid peroxides are maintained at physiological levels by sophisticated intracellular antioxidant systems (e.g., GPX4/GSH, FSP1/CoQ10, GCH1/BH4), which are generally inhibited or down-regulated during ferroptosis [45].

2.3. Lipid Peroxidation by Non-Enzymatic and Enzymatic Reactions

Ferroptosis is uniquely characterized and driven by overwhelming membrane lipid peroxidation, which leads to altered ion fluxes and ultimately to plasma membrane permeabilization [12]. Overall, the situation is quite flexible: a wide range of lipid substrates and starting sources may be able to support the lipid peroxidation events that ultimately lead to ferroptotic cell death. More specifically, the generation of toxic lipid-derived peroxide species may result from non-enzymatic or enzymatic processes, both involving different forms of catalytically active iron. Evidence for the important role of lipid peroxidation in the execution of ferroptosis also comes from inhibition studies. Many potent and specific inhibitors of ferroptosis terminate the lipid peroxidation process by acting as lipophilic radical-trapping antioxidants, thus bolstering the link between lipid membranes and ferroptosis.
The chemistry of lipid peroxidation is well understood and has been extensively reviewed elsewhere [44]. Here, we will briefly mention non-enzymatic or enzymatic processes contributing to the ferroptotic process (a more detailed discussion is given in Section 3). Different phases of initiation, propagation, and termination are involved in the lipid peroxidation mechanism. Anyway, the generation of toxic lipid-derived peroxides encompasses general reaction schemas that are similar in non-enzymatic and enzymatic processes: the oxidation starts with the abstraction of a bis-allylic hydrogen and consequent formation of lipid radical species, and after the addition of molecular oxygen, they become peroxyl radicals and then hydroperoxides. Numerous types of ROS/RNS (see Section 3.1), particularly in the presence of iron, can initiate lipid peroxidation and push ferroptosis. Mitochondria are also sites of substantial ROS generation that may contribute to the initiation of lipid peroxidation, but their role remains controversial [34,46]. Enzymes that can oxidize lipids include members of the lipoxygenase (LOX) and cyclooxygenase (COX) families and oxidoreductase NADPH-cytochrome P450 reductase (POR) isoforms, as well as fatty acyl-CoA reductase1 (FAR1) (as discussed in Section 3.1.3). However, since in ferroptosis, PUFA phospholipids have been found to be peroxidation substrates instead of free PUFA, LOXs appear to be the most likely candidate enzymatic catalysts of ferroptotic peroxidation based on the observation that COXs oxidize free rather than esterified PUFA [20,41]. In addition, it is to be highlighted that enzymatic peroxidation is highly selective for specific substrates and products, in contrast to the random profile observed for free radical peroxidation. Therefore, even though the mechanistic reactive intermediates of these peroxidation reactions may be similar, the fundamental questions of regulation, specificity, and selectivity still need better understanding, since this will have a significant impact on the development of novel pro- and anti-ferroptotic therapeutic approaches [47]. Accordingly, ferroptosis inhibitors such as ferrostatin-1 (Fer-1) and liproxstatin-1, as well as endogenous antioxidants like α-tocopherol, GSH, and N-acetylcysteine (NAC), inhibit lipid peroxidation, thus demonstrating that ferroptosis induction requires lipid peroxidation and iron-dependent ROS.
As a kind of PUFA-hydroperoxide-dependent cell death, ferroptosis can be theoretically initiated/carried out in all biological membranes, including mitochondria, endoplasmic reticulum (ER), peroxisomes, Golgi apparatus, and lysosomes. Previous reports have observed the activation of the ER stress-related unfolded protein response during ferroptosis [48,49]. To identify the membranes of subcellular structures essential for ferroptosis and unveil the possible sequence of peroxidation, A. N. von Krusenstiern et al. performed a deep evaluation of the structure, activity, and distribution of ferroptosis inhibitor/inducers using novel, powerful technologies [43,50]. In that paper, the authors identified ER membranes as the initial and crucial sub-compartment of lipid peroxidation, even if various other subcellular membranes can produce lipid peroxidation. Thus, the authors suggested an ordered progression: initially lipid peroxides accumulate in the ER membrane and later in the plasma membrane; however, it is not clear if the peroxidation can spread to other membranes, or if it occurs independently at different stages and with different rates.

2.4. Ferroptosis and Physio-Pathological Processes

Many physio-pathological processes have been correlated with ferroptosis [2,51], including aging and neurodegeneration, senescence, tumorigenesis, blood diseases, kidney disorders, and ischemia–reperfusion injuries (Figure 3).
Figure 3. Physiological and pathological processes related to ferroptosis. For each disease, the main features are reported. Created with BioRender.com (accessed on 30 January 2024).

2.4.1. Ferroptosis in Aging

Aging is a natural life process characterized by a gradual deterioration of physiological mechanisms, resulting in impaired functions of the organs and increased morbidity and mortality due to a combination of environmental and genetic factors. Hallmarks of aging processes include overproduction of ROS species, exhaustion of antioxidant systems, imbalance in oxidation and antioxidant processes [52], and the up-regulation of oxidative stress-induced pro-inflammatory mediators [53,54]. More recently, aging has also emerged as a process related to dysregulated iron homeostasis with intracellular iron stores accumulating with increasing age [55]. Therefore, since the discovery of the ferroptotic mechanisms, a link between aging and ferroptosis has been postulated in a variety of age-related processes, including cancer, neurodegenerative, and cardiovascular diseases [56]. As an example, in this section, we briefly introduce the impact of ferroptosis on these diseases.

2.4.2. Ferroptosis in Cancer Cells

Many links correlate tumors with ferroptosis. Active metabolism in cancer cells is causative of high ROS production [3]. Hallmarks of cancer metabolism also include elevated iron requirements that under oxidative stress make cancer cells more susceptible to ferroptosis as compared to their normal counterparts. In addition, ferroptosis is regulated by numerous tumor-related genes and signaling pathways [57,58]. Several mechanisms involved in ferroptosis, including system Xc-, GPX4, lipid peroxidation, and GSH metabolism, mediate biological processes such as oxidative stress and iron overload and appear to be dysregulated in many cancer types [59,60,61,62].
However, given the extraordinary complexity and heterogeneity of this group of disorders, sensitivity to ferroptosis may vary greatly among different types of cancer cells. For example, p53, which exerts a critical role in inhibiting tumorigenesis and other cancer processes such as invasion, metastasis, and metabolism, has been reported to control ferroptosis-related genes to prevent tumor growth [63,64]. However, as discussed in detail in Section 4.6 it recently emerged that p53 has opposing effects on ferroptosis regulation in different tumor cells. Thus, ferroptosis susceptibility may be modulated by p53 in a tissue-and cell type-specific manner.
More recently, ferroptosis has been proposed as a strategy to overcome drug resistance in cancer cells, which are often resistant to apoptosis and standard therapies [65,66]. However, cancer cells may employ a variety of genetic or epigenetic strategies to combat these metabolic and oxidative stresses [67]. For example, they may up-regulate the antioxidative transcription factors nuclear factor, erythroid derived 2, and like 2 (NRF2) or increase the expression of solute carrier family 7 member 11 (SLC7A11), which reduces the cell’s vulnerability to ferroptosis. Therefore, whether a cancer cell is more sensitive or resistant to ferroptosis induction depends on its specific genetic background. Additionally, through adaptive mechanisms, ferroptosis may contribute to immunity against cancer. Therefore, because ferroptosis can be an immunogenic or immunosuppressive type of cell death, its function in cancer is rather controversial and needs further studies [68].

2.4.3. Ferroptosis in Leukemia

Normal hematopoiesis requires iron, the depletion of which impairs the proliferation and differentiation of hematopoietic cells [69]. Leukemic cells have higher iron concentrations and transferrin expression than other cancer cells and this facilitates the accumulation of iron-derived damage, especially to membrane lipids. Accordingly, a large body of work has recently highlighted the role of ferroptosis in acute myeloid leukemia (AML). Metabolic pathways typically altered in AML and related to ROS/RNS production include enzymes like nitric oxide synthase (NOS), CYP, NAD(P)H oxidase (NOX), and COX (reviewed in [70]). The high frequency of ROS/RNS overproduction in leukemia clearly implies that they are related to the etiology of this disease [71]. Oxidative stress plays a dual role in the development of hematologic malignancies [72]. Chemotherapeutic drugs induce apoptosis by producing high levels of ROS, which suppress tumor growth [73]. Low levels of ROS, on the other hand, protect AML cells from apoptosis and increase treatment resistance, cell migration, growth, and proliferation [61,74]. AML cells are particularly sensitive to iron overload, and although there is strong evidence that transferrin is highly expressed in these cells with increased binding activity, the exact effect of transferrin on AML cells is unclear [70]. Therefore, ferroptosis is emerged as a therapeutic target in leukemia. Indeed, as reviewed by Weber et al. [75], there are four main categories under which current methods of treating AML fall: iron chelators, modification of iron metabolism-related proteins, production of ferroptosis, and administration of antileukemic drugs through ferritin [75]. Of note, all of these categories are based on the modulation of iron metabolism.

2.4.4. Ferroptosis in Heart Failure

Heart failure (HF) is a worldwide epidemic condition that is becoming increasingly common and endangers people’s health. Cardiomyocytes play a key role in maintaining the physiology of the heart and the loss of these caused by cardiovascular disease can speed up the development of HF [76]. During HF, there is an increase in LIP production causing a release of free iron in the myocardium that can alter redox balance and promote ferroptosis in cardiomyocytes [77]. Studies have shown that ferroptosis can also cause a systemic inflammatory response that induces hypertrophy and the death of cardiomyocytes and leads to chronic adverse ventricular remodeling [78,79]. Thus, inhibition of ferroptosis can prevent inflammation and consequently, cardiomyocyte death, while preserving normal cardiac function [80]. A recent investigation revealed that in cardiomyocytes (H9c2 cells) treated with isoprenaline or erastin in a rat HF model induced by aortic banding there was an excess of lipid peroxidation, elevated iron content, and decreased cell viability [81,82]. Also, ferritin plays a key role in maintaining iron homeostasis in the heart. In fact, ferritin H-deficient mice showed reduced expression of SLC7A11 in heart cells, while selective overexpression of SLC7A11 increased GSH levels and prevented cardiac ferroptosis [83]. Research has thus uncovered the regulatory mechanisms and function of ferroptosis in cardiac disease, offering novel treatment options and insights. Nevertheless, not enough is known about ferroptosis’s function in this area to create a successful treatment plan.

2.4.5. Ferroptosis in Neurodegenerative Diseases

Among age-related conditions, neurodegenerative diseases are frequent causes of disability and among the most common causes of death worldwide. The abnormal metabolism of lipids, of which the brain is especially rich, leads to ferroptosis, which can greatly contribute to acute damage to the central nervous system. Indeed, dysregulation of iron homeostasis and excessive ROS in the brain are common hallmarks of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) [84]. When neurons die, their iron-containing inclusions are released. This condition generates a vicious circle: in the absence of efficient iron removal systems, iron accumulates in brain areas and promotes the generation of ROS species, causing other neurons to undergo ferroptosis and further reducing the levels of antioxidant defenses [85,86]. Consequently, with iron-dependent oxidative stress serving as a key indicator of cellular ferroptosis, the notion that ferroptosis is inextricably linked to neurodegenerative diseases is receiving growing support. As a consequence, controlling ferroptosis has become a new treatment option for these disorders. In the case of AD, iron chelators delay the disease onset by preventing neuronal death [87,88].
In Parkinson’s disease, the age-related reduced capacity to regulate iron absorption also contributes to iron overload, which is common among older people. Notably, ferroptosis features like iron accumulation, GSH depletion, lipid peroxidation, and an increase in ROS species have been observed in PD. Accordingly, inhibitors of ferroptosis have the potential therapeutic role to protect the nervous system in PD [89,90,91].

4. Antioxidant Systems and Transcription Factors

Although the molecular mechanisms and/or metabolic pathways governing ferroptosis are still poorly understood, this process seems to be under the control of numerous transcription factors (TFs) [14,15], with most of them acting as transcriptional modulators of specific genes involved in redox homeostasis and lipid peroxidation processes, as well as in iron/heme metabolism and inflammation. Many TFs work by reinforcing the antioxidant systems, including the GPX4/glutathione/cysteine pathway, mevalonate pathway, and ferroptosis inhibitory protein 1 (FSP1)–coenzyme Q10 (CoQ10) pathway, therefore preventing ferroptosis, whereas others foster ROS/RNS production, lipid oxidation, and iron accumulation, therefore pushing ferroptosis [73] (Figure 6).
Figure 6. Transcription factors and their redox-related gene targets in ferroptosis. For each transcription factor, DNA regulatory elements, target genes, and their positive or negative effects on ferroptosis are shown. Created with BioRender.com (accessed on 30 January 2024).

4.1. NRF2 Pathway

NRF2 is one of the most important transcription factors in ferroptosis sensitivity that exerts an anti-ferroptotic effect by modulating the expression of many genes involved in antioxidant response and iron metabolism as well as in lipid homeostasis (reviewed in [283]). NRF2 function is mainly regulated by the Kelch-like ECH-associated protein 1 (Keap1). Keap1 plays a crucial role in basal conditions to promote NRF2 ubiquitination and proteasome degradation, thus keeping NRF2 at low levels. Under stressed conditions, Keap1 is inactivated and consequently de novo synthesized NRF2 can move into the nucleus, where it forms heterodimers mainly with the small MAF (musculoaponeurotic fibrosarcoma, MafF, MafK, and MafG) proteins to bind the antioxidant response elements (AREs) present in its target gene promoters, activating their transcription. Nrf2 can also form heterodimers with other transcription factors, thus extending the repertoire of its gene targets. Keap1 inactivation results in NRF2 stabilization and consequent upregulation of NRF2 target genes [284], a condition that favors resistance against ferroptosis, as demonstrated by Cao et al. through genome-wide human haploid cell genetic screening [285]. Importantly, although the dominant regulation of NRF2 occurs at the protein level, NRF2 expression is also modulated at the transcriptional level by different oncogenes, such as KRAS, BRAF, and c-MYC [286], and thus many cancer cells display constitutively activated NRF2 [287]. Furthermore, NRF2 enhances the resistance of cancer cells to chemotherapeutic drugs. Accordingly, loss of NRF2 confers increased sensitivity to electrophilic, xenobiotic, metabolic, and ferroptosis inducers in cancer cell lines [288].
A pioneering study in 2016 demonstrated that during treatment with various ferroptosis inducers (e.g., erastin, BSO, and sorafenib), the NRF2 protein levels were increased in hepatocarcinoma cell lines [289]. This was caused by the inactivation of Keap1 through the p62/sequestosome1 pathway (allowing NRF2 stabilization [284]). It was demonstrated that NRF2-dependent transcriptional activation of genes involved in heme (i.e., HO-1), iron (i.e., FTH1), and ROS metabolism (i.e., NQO1) could protect against ferroptosis and that NRF2 inhibition potentiated the sensitivity to ferroptosis in vitro and in tumor xenograft models [289]. In general, NRF2 can control ferroptosis cascades by modulating the expression of multiple genes involved in the regulation of iron levels, in the synthesis of GSH, and in the removal of lipid hydroperoxides, as well as those of the FSP1-dependent CoQ system [290]. NRF2 buffers the labile iron pool by upregulating ferritin gene expression, which favors iron storage and modulates the expression of ferroportin, the only known exporter of iron in mammals, therefore protecting against iron overload-induced oxidative stress and by inducing metallothionein 1G expression, which plays an essential role in the detoxification of divalent metal ions [291]. A recent work demonstrated that NRF2 controls the synthesis and degradation of ferritin by directly inducing the expression of the HERC2 gene, containing functional AREs in its promoter and coding for an E3 ubiquitin ligase, and by indirectly regulating autophagic protein VAMP8 levels [292]. In that paper, the authors demonstrated that NRF2 can contribute to iron homeostasis through three mechanisms: (a) ferritin synthesis through the NRF2–HERC2–FBXL5–IRP1/2 axis; (b) ferritin degradation via ferritinophagy through the NRF2–TFEB–VAMP8–cascade, and (c) ferritin recruitment to the autophagosome via the NRF2–HERC2–NCOA4 axis. Indeed, ablation of NRF2 increases apoferritin in the autophagosome, promotes LIP accumulation, and consequently enhances sensitivity to ferroptosis in human ovarian cancer cells and preclinical models [292]. In addition, NRF2 controls iron levels through regulation of heme metabolism-related genes, including (i) HO1, which degrades heme, (ii) ABCB6, which transports heme/porphyrin across intra- and extra-cellular membranes; (iii) FECH (ferrochelatase), which inserts iron into protoporphyrin IX, (iv) SLC48A1, which carries heme from lysosomes to cytoplasm, and (v) BLVRA/B (biliverdin reductase), which catalyzes the second step in heme degradation (biliverdin reduction to bilirubin). NRF2 intervenes in lipid protection by regulating a set of genes involved in different aspects of lipid metabolism. Firstly, NRF2 can directly regulate the GPX4 protein content via binding to the ARE element present in its promoter [293] or indirectly by increasing the expression of ARE-target genes (containing promoter ARE sequences) coding for enzymes that provide endogenous thiol resources, including GSH-synthesizing and -regenerating enzymes (GCLC/GCLM, GSS, and GSR), cystine transporters (SLC7A11), and enzymes synthesizing cysteine, as well as genes encoding components of antioxidant systems like TRX and TXNRD1 and metabolic enzymes [glucose-6·phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (PGD), isocitrate dehydrogenase 1 (IDH1), and malic enzyme 1 (ME1)] that produce NADPH, a cofactor necessary to reconstitute reduced GSH, TRXs, and PRDXs from their disulfide forms, thus ensuring the reduced state of cysteine thiols and FSP1 activity. Other genes regulated by NRF2 are the AKR1C family members and MGST1, which contribute to the detoxification of lipid-derived reactive aldehydes and lipid peroxides, as well as FSP1, producing reduced coenzyme Q10 that traps lipid peroxides. Concerning lipid content, NRF2 regulates the expression of genes involved in lipid metabolism by down-modulating the expression of genes involved in lipogenesis and up-regulating genes involved in lipolysis as well as genes involved in lipid transport and uptake, thus influencing ferroptosis susceptibility through controlling lipid composition. Recently, Takahashi et al., by using three-dimensional (3D) cancer spheroid models from lung cancer cell lines (A549 and H1347 bearing hyperactivated NRF2), demonstrated that NRF2 prevents lipid peroxidation through reducing ROS levels in inner spheroid cells, which are more susceptible to ferroptosis, as proven by the same authors [294]. CRISPR-Cas9 screens identified, along with NRF2 and MAFG, three NRF2-dependent genes of the glycolytic/pentose phosphate pathway, as well as GPX4, as common hits required for growth whereas NRF2 silencing renders spheroid cells highly vulnerable to ferroptosis, in spite of a compensatory GPX4 increase, indicating the predominant role of NRF2 in shielding against redox stress [294]. NRF2 can also form heterodimers with members of the AP-1 family, like c-JUN, or ATF members, acting on ARE-target genes [295,296]. More recently, Zhang et al. demonstrated in lung cancer that the induction via NRF2/c-JUN-CBS expression of the transsulfuration pathway is important in the protection against erastin- or RSL3-induced ferroptosis [297]. This pathway acts through the transcription factor nuclear receptor subfamily 0 group B member 1 (NR0B1, also known as DAX1 dosage-sensitive sex reversal-AHC critical region on the X-chromosome gene 1) to push cysteine production. Indeed, manipulation of NR0B1 levels affected ferroptosis by influencing GSH, ROS, MDA, and iron levels. RNA-seq analysis in A549 lung cells harboring knocked-down or overexpressed NR0B1 demonstrated that NR0B1 expression positively correlated with NRF2, c-JUN, and CBS by directly binding to the promoters of NRF2 and c-JUN, which in turn form functional dimers that promote CBS expression. Implantation in mice of lung cancer cells A549 harboring depleted NR0B1 further proved that tumor growth was restrained in the absence of NR0B1 and favored RSL3-induced ferroptosis [297]. However, NRF2 signaling could be highly context-dependent; for example, GPX4 could be either upregulated or downregulated by NRF2 in different cancer cell lines [260], making NRF2 a multifaceted modulator of the anti-ferroptotic response [298]. It is important to underline that most of the above genes can also be transcriptionally regulated by different transcription factors. For example, SLC7A11 can be induced by ATF4 (activating transcription factor 4) and inhibited by the tumor suppressor p53 or ATF3 (activating transcription factor 3) under basal conditions [299].

4.2. ATF Signaling

Activating transcription factor 2 (ATF2/CREB2) is a multi-faceted leucine zipper transcription factor that binds to the cAMP responsive element (CRE). Generally, in response to many cell stress conditions, preferentially oxidative stress, ATF2 is phosphorylated by different kinases, including JNK and p38/MAPK. Then, phosphorylated ATF2 translocates to the nucleus where, in combination with different interactors such as Fos, c-Jun, CREB, and ATF1, it activates its gene targets [300]. Numerous evidence indicates that ATF2 can act either as an oncogene or antioncogene in different cancer types depending on its expression level and/or subcellular localization. A recent study of Xin Xu et al. reported that ATF2 is elevated in gastric cancer (GC) [301]. Further experiments in GC cells demonstrated that ATF2 knockdown inhibited malignant phenotypes and potentiated ferroptosis induced by sorafenib, a protein kinase inhibitor drug, causing endoplasmic reticulum stress, GSH depletion, and iron-dependent lipid radical accumulation, while overexpression of ATF2 reduced sorafenib-induced ferroptosis sensitivity. Specifically, ATF2 protects GC cells from sorafenib-mediated ferroptosis by raising the expression of the heat shock protein-110 (HSPH1, also called HSP105 or HSP110), which physically interacts with SLC7A11 and prevents its degradation. Indeed, ATF2 can bind the HSPH1 promoter region, consequently activating its transcription, whereas HSPH1 is downregulated following ATF2 knockdown. HSPH1 silencing in gastric adenocarcinoma AGS cells stably overexpressing ATF2 showed downmodulation of SLC7A11 at the protein but not at the mRNA level, thus highlighting that HSPH1 can interact with and improve SLC7A11 stability in GC cells, thus contributing to the uptake of cystine required for GSH synthesis [301]. Furthermore, ATF2 activated through the JNK1/2 pathway plays a role in attenuating ferroptosis induced by treatments with BETi (inhibitors of bromo- and extra-terminal domain) in cancer cells and this was mediated by increased expression of NRF2 [302]. In fact, while depletion of ATF2 increased the ferroptosis induced by BETi treatment in MB-231 cells, ATF2 modulation does not affect BETi-induced ferroptosis in NRF2-silenced cells [302]. It was also demonstrated that ATF2 plays a crucial role in maintaining GSH homeostasis in human mesenchymal stem cells (MSCs) by modulating the CREB1–NRF2 redox homeostasis signaling pathway [303]. In MSC cells, ascorbic acid 2-glucoside (AA2G) treatment increased the mRNA levels of NRF2 and several genes related to GSH synthesis (GCLC and GCLM) and redox cycling (GSR and PRDX1) previously reported as targets of the CREB1–NRF2 pathway. ATF2 knockdown impaired the AA2G-mediated induction of the GSH-related genes targeted via the CREB1–NRF2 pathway and counteracted the nuclear translocation of NRF2 protein, suggesting an interplay between the ATF2 and CREB1–NRF2 signaling cascades in MSCs [303].
ATF3 is a stress-inducible transcription factor and a member of the activation transcription factor/cAMP responsive element-binding (CREB) protein family. It is expressed at low levels in normal conditions but it can be upregulated by a variety of stress signals, including hypoxia, cytokines, DNA damage, oxidative stress, endoplasmic reticulum stress, and cell injury. A growing body of evidence shows that ATF3 modulates anti-inflammatory and immune response, oncogenesis, and metabolic homeostasis [304,305]. ATF3 regulates gene expression by binding to consensus ATF/CREB cis-regulatory elements in DNA targets via a basic-region leucine-zipper (bZIP) domain. In addition, ATF3 can interact with its family members and other proteins, such as p53 and Tip60, and it regulates cellular functions independently of its transcriptional activity. Regarding ferroptosis, ATF3 can suppress system Xc- and predispose cells to ferroptosis by repressing SLC7A11 expression.
In detail, Liyuan Wang et al. demonstrated that ATF3 over-expression sensitized human fibrosarcoma HT1080 cells to erastin-induced ferroptosis death by causing an excessive increase of lipid peroxide levels. Conversely, ATF3 knockout dramatically suppressed erastin-induced ferroptosis and lipid peroxidation with a negligible effect on the amount of released glutamate and decreased intracellular GSH levels. By genome-wide ChIP-seq analysis and gene expression analysis, the authors revealed that ATF3 binds the SLC7A11 promoter region proximal to the transcription start site and represses its expression. Interestingly, lentiviral-mediated SLC7A11 expression in ATF3 over-expressing fibrosarcoma cells restored system Xc- function and impaired ATF3-mediated ferroptosis. Thus, ATF3 induces ferroptosis by suppressing system Xc- through SLC7A11 expression downregulation [306].
Furthermore, Yilan Li et al. showed that ATF3 also promotes sorafenib-induced ferroptosis by suppressing SLC7A11 in cardiomyoblasts. In fact, ATF3 was induced upon sorafenib treatment and, notably, knockdown of ATF3 failed to restrain SLC7A11 expression, decreased cellular ROS and lipid peroxides, and preserved the ΔΨm in sorafenib-treated H9c2 cardiomyoblasts [307]. Xi Chen et al. recently demonstrated that ATF3 activation mediated by sirtuin1 (SIRT1) deacetylase decreased SLC7A11 and GPX4 expression in glioma cells treated with the GPX4 inhibitor RSL3, causing ferroptosis, associated with intracellular ferrous iron increase and lipid peroxidation [308]. They demonstrated that manipulation of SIRT1 activity either through activator (SRT2183) or inhibitor (EX527) treatment, or decreasing SIRT1 levels by siRNA, impacted RSL3-triggered SLC7A11 and GPX4 expression; in line with this, ATF3 siRNA impaired the RSL3-SLC7A11 and GPX4 downregulation of expression and reduced the sensitivity to RSL3-induced ferroptosis [308].
ATF4 is another bZIP stress-responsive transcription factor of the ATF/CREB family that binds to conserved cAMP-responsive element (CRE) to modulate the transcription of target genes. ATF4 expression is activated in response to numerous stress signals such as amino acid starvation, anoxia/hypoxia, and endoplasmic reticulum stress [309]. Albeit ATF4 could play a dual role in favoring or exacerbating cell death, many studies have demonstrated a protective role of ATF4 in ferroptosis as a compensatory factor for SLC7A11 expression. In pancreatic ductal carcinoma, ATF4 has been demonstrated to have a protective effect in ferroptosis by transcriptional activation of SLC7A11 and by maintaining GPX4 stability through induction of the heat shock protein family A (Hsp70) member 5 (HSPA5), an ER-associated molecular chaperone [310]. In mouse models and melanoma cells deficient in xCT, induction of ATF4 and NRF2 under conditions of cystine- or GSH-depletion enabled a compensatory response by increasing cysteine synthesis via the transsulfuration pathway and the antioxidant system via the thioredoxin pathways [311]. In the hepatocarcinoma context, ATF4 activation sustained by the YAP/TAZ pathway induced SLC7A11 to protect against sorafenib-induced ferroptosis [312]. More recently, He et al. demonstrated that young MUP-uPA mice (undergoing hepatic ER stress under a high-fat diet (HDF)) lacking hepatocyte ATF4 expression exhibited enhanced liver injury and disruption of redox homeostasis associated with lower intracellular GSH and decreased mRNA levels of SLC7A11, SLC7A5, and superoxide dismutase 2 (SOD2), sensitizing cells to ferroptosis [313]. In fact, ATF4 ablated-cultured hepatocytes are more sensitive to RSL3 treatment, and in vitro reconstitution of either ATF4 or SLC7A11 protected ATF4-deleted hepatocytes against RSL3-mediated ferroptosis. Luciferase assays demonstrated that ATF4 stimulates SLC7A11 expression by cooperating with NRF2. Indeed, ATF4 does not induce SLC/A11 in the absence of NRF2 [313]. Finally, liver-specific ATF4 deletion provoked lipid peroxidation and hepatic damage, and accelerated liver cancer in HFD-fed MUP-uPA mice that could be counteracted by forced SLC/A11 expression [313]. Therefore, ATF4 may interact with NRF2 to transcriptionally activate multiple protective factors against ferroptosis, including SLC7A11. Indeed, additional experiments revealed that ATF4-dependent tumor-promoting effects are mediated by transcriptional targeting the glutamate antiporter xCT/SLC7A11, and the knockdown of ATF4 increases the ferroptosis cell death induced by different ferroptosis agents, including sorafenib, erastin, and RSL3, associated with lipid peroxidation accumulation [299]. In other studies, ATF4 expression was found to sustain the aggressiveness of primary brain tumors by enhancing growth, angiogenesis, migration, and anchorage-independent cell growth and also by conferring a multidrug-resistance phenotype, whereas ATF4 knockdown reduced the malignancy features in human glioma cells [299].

4.3. TFAP2 Pathway

Another family of transcription factors involved in the attenuation of ferroptosis is related to the transcription factor AP-2, comprising five members (TFAP2A–E) [314]. The transcription factor alpha (TFAP2A) has been linked to NRF2 signaling. Indeed, TFAP2A silencing downmodulates in vitro the expression of NRF2 and NRF2-dependent genes linked to ferroptosis, including HO-1, FTH1, and NQO1 [315]. TFAP2 gamma (TFAP2C) also prevents ferroptosis by regulating the transcription of various genes under different conditions. Ishraq Alim et al. demonstrated that TFAP2, activated in neurons by supraphysiological levels of selenium (Se), together with SP1 achieved antioxidant GPX4 expression to protect neurons from ferroptosis and improved behavior in a hemorrhagic stroke model. In particular, ChIP assays showed that neurons exposed to Se significantly increased the TFAP2 and SP1 occupancy on the Se-responsive region of GPX4, which binds the same or adjacent DNA binding sites. In addition, overexpression of TFAP2 or SP1 regulated the mRNA expression of several other genes induced by ferroptosis stimuli, such as GPX3, TXNRD1, SELK, and MSRB1, and protected neurons from hemin or HCA-induced ferroptosis [316].
Recently, Xingkang Jiang et al. reported that TFAP2 activates the transcription of the prostate cancer-associated transcript 1 (PCAT1), an oncogenic long noncoding RNA [317]. PCAT1 was upregulated in docetaxel (DTX)-resistant PCa prostate cancer cells and in prostate cancer (PCa) patients, whereas PCa patients with higher serum PCAT1 levels had an unsatisfactory response to DTX chemotherapy. Besides, PCAT1 up-regulation decreased erastin- and DTX-induced cytotoxicity in PCa cells. Conversely, prostate cancer cells with PCAT1 knockdown developed tolerance toward ferroptosis induced by erastin or DTX treatments, reducing the lipid ROS content and iron overload. Investigation of the molecular mechanism of TFAP2C-mediated ferroptosis resistance demonstrated that TFAP2C knockdown efficiently inhibited the transcription of PCAT1 and SLC7A11. Since TFAP2C is able to bind only the PCAT1 promoter, the decrease of SLC7A11 expression is PCAT1-mediated. In fact, the authors observed a downmodulation of SLC7A11 mRNA and protein following PCAT1 knockdown and, also, showed that PCAT1 silencing decreased SLC7A11 expression in xenograft mouse models. Moreover, RNA pull-down and immunoprecipitation assays revealed that PCAT1 interacts with c-Myc protein, increasing its stability and consequently c-Myc activates SLC7A11 transcription by binding to its promoter. Finally, PCAT1 also positively regulates SLC7A11 expression by interacting with and sponging miR-25-3p, which can target the 3′UTR of SLC7A11, as proven by luciferase assays. Thus, PCAT1, activated by TFAP2C, in turn, hinders ferroptosis cell death through regulation of the c-Myc/miR-25-3p/SLC7A11 signaling pathway [317].

4.4. JAK-STAT Pathway

Multiple studies have indicated that alteration of redox circuits and increased lipid peroxidation can activate inflammatory pathways eliciting pro-inflammatory cytokines that, in turn, aggravate oxidative stress leading to excessive lipid peroxidation [318]. Janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-κB (NF-κB), inflammasome, cGAS-STING, and MAPK signaling pathways are indeed key regulators of ferroptosis.
JAK/STAT signaling comprises membrane receptors that after binding with ligands and dimerization, recruit constitutively associated non-receptor kinases called Janus kinases (JAKs), which phosphorylate the receptors, yielding docking sites for cytosolic STAT transcription factors (STAT1-4, STAT5a, STAT5b, and STAT6) that also become phosphorylated and activated. Phosphorylated STATs (pSTATs) bind to each other, forming homo- or hetero-dimers that translocate into the nucleus to mediate gene transcription by binding to specific promoter regions (reviewed in [319]). The JAK/STAT pathway mediates signal transduction for numerous growth factors/hormones and cytokines (>50 ligands), in particular interferons (IFNs) and interleukins (ILs) regulating differentiation, proliferation, apoptosis, and cell survival, depending on the specific signals and cellular context and driving inflammatory diseases, lymphomas, leukemias, and different solid tumors [320,321]. In addition, other signaling pathway members and/or other regulatory circuits can regulate JAK/STAT signaling by pushing or inhibiting STAT phosphorylation and translocation [321]. Increasing data indicate that STATs can be oncogenes or tumor suppressor factors, and any treatment based on STAT modulators should take the multifaced function of these transcription factors in different tumors into account [322].
The JAK/STAT pathway activated by IFNγ, which binds two receptor subtypes, IFN-γ receptor (IFNGR)-1 and-2, participates in ferroptosis. The work of Tsoi et al. reported that IFNγ under erastin treatment has a role in potentiating ferroptosis of human melanoma cells through STAT1 increases [323]. Next, Wang et al. demonstrated in co-cultured cell systems that IFNγ (released by effector CD8+ T cells) sensitizes tumor cells to ferroptosis induced by RSL3 or erastin by reducing Xc- system activity, consequently depleting GSH and increasing lipid peroxidation/ferroptosis of tumor cells [324]. In this context, IFN-γ directed the binding of STAT1 to the SLC7A11 promoter, as demonstrated by ChIP assays. In line with this, STAT1 deficiency abolished the IFN-γ contribution and cyst(e)ine depletion by cyst(e)inase (an engineered enzyme that breaks down extracellular cysteine/cystine) increases T cell-mediated ferroptosis [324].
Furthermore, IFNγ enhanced erastin-induced ferroptosis, increasing lipid peroxidation, iron, mitochondrial damage, and ROS in adrenocortical carcinoma cells [325]. In particular, Western blot, RT-qPCR, and immunofluorescence analyses showed that IFNγ, through STAT1/STAT3 and interferon regulatory factor 1 (IRF1) activation, enhanced erastin-induced ferroptosis associated with repression of SLC7A11 expression. Accordingly, IFNγ treatments failed to increase lipid peroxidation and mitochondrial damage in adrenocortical carcinoma cells with SLC7A11 over-expressed or STAT1 inhibited [325]. Another work in hepatocellular carcinoma cells demonstrated that IFNγ treatment sensitized Bel7402 and HepG2 cells to ferroptosis inducers (erastin or RSL3) by reducing the GSH content and increasing lipid peroxidation mediated by the JAK/STAT pathway that reduced mRNA/protein expression of SLC3A2 and SLC7A11, consequently inhibiting system Xc- activity, provoking ROS increase and ΔΨm decrease. Of note, IFN-γ treatment in vivo abated the growth of xenograft tumors through increasing lipid oxidation [326].
Differently from the cancer context, age-related macular degeneration (AMD) causes cell death in retinal pigment epithelium (RPE) that can be coupled to IFN-γ increases. The work of Wei et al. demonstrated indeed that IFN-γ promoted ferroptosis in human retinal pigment epithelial cells (ARPE-19) and this was accompanied by iron and ROS increase, lipid peroxidation, and GSH depletion [327]. These effects were linked to inhibition of SLC40A1 expression (which exports iron), and to activation of the JAK1/2-STAT1 pathway that lowered SLC7A11/GPx4 and GSH levels, as demonstrated with specific inhibitors. These results were further confirmed in vivo by using IFN-γ-treated mice as well as AMD models generated by sodium iodate treatment that provokes retinal degeneration, suggesting that inhibition of ferroptosis (and IFN-γ) could be a possible target for AMD [327].
In a previous study, Gao et al. demonstrated that STAT3 is a positive regulator of ferroptosis through activation of lysosomal-dependent cell death in human pancreatic ductal adenocarcinoma (PDAC) cell lines. Pharmacological or siRNA inhibition of STAT3 interferes with erastin-induced ferroptosis. Indeed, lysosomal dysfunction induced by selective cathepsin inhibition or by vacuolar-type H+-ATPase hampering restricted erastin-induced ferroptosis in PDAC cells. Finally, the authors displayed that STAT3-mediated cathepsin B (CTSB) expression was required for ferroptosis [328].
On the contrary, Shumin Ouyang et al. established a negative STAT3–ferroptosis regulatory axis in gastric cancer. In particular, the authors demonstrated by ChIP-qPCR analysis that STAT3 binds to the promoter regions of three ferroptotic genes, namely GPX4, SLC7A11, and FTH1, to positively regulate their expression [329]. STAT3 knockdown in gastric cancer cells provoked a significant inhibition of GPX4, SLC7A11, and FTH1 at both the mRNA and protein levels, and also increased lipid peroxidation and ROS, and enhanced intracellular Fe2+, thus reducing the GSH/GSSG ratio in gastric cancer cells. A similar effect was observed in gastric cancer cells treated with the STAT3 inhibitor W1131 caused by reduced STAT3 occupancy on the GPX4, SLC7A11, and FTH1 promoters. Interestingly, the combination of W1131 and 5-FU (5-fluorouracil) re-sensitizes chemo-resistant cancer cells to 5-FU. Thus, these data underlie the importance of the use of JAK/STAT inhibitor drugs to re-establish the sensitivity of cells to ferroptosis, thus increasing the chemotherapy response [329].
Other evidence that STAT3 inhibition may induce ferroptosis comes from the work of Liu et al. [330]. They reported that cisplatin-resistant osteosarcoma MG63 and Saos-2 cells have elevated pSTAT3 and NRF2 levels. Treatment with erastin and RSL3 decreased the viability of cisplatin-resistant cells accompanied by increased levels of ROS, lipid peroxides, MDA, and decreased GPx4 protein levels. In addition, treatments with BP-1-102, a STAT3 inhibitor, abolished resistance to cisplatin, indicating that the STAT3/NRF2/GPx4 signal has a critical function in the drug resistance of osteosarcoma cells [330]. Also, Yi Luo et al. found that the flavonoid bavachin inhibits the viability of MG63 and HOS osteosarcoma cell lines by inducing ferroptosis through the STAT3/p53/SLC7A11 axis [331]. The authors showed that bavachin treatment down-modulated GPX4 and SLC7A11 expression, increased p53 protein levels, and inhibited STAT3 activation. It was also demonstrated that bavachin increased the intracellular ferrous iron concentration and the ROS, and MDA levels, consequent to SLC7A11 downregulation and p53 upregulation, this latter being mediated by STAT3 inactivation. Accordingly, SLC7A11 overexpression decreased the features of bavachin-induced ferroptosis, and the use of PFT-α, a p53 inhibitor, upregulated SLC7A11, thus attenuating the bavachin-induced ferroptosis. Finally, osteosarcoma cells overexpressing STAT3 failed to upregulate p53 expression in response to bavachin and no longer induced ferroptosis. Therefore, STAT3 inhibition by bavachin caused p53 upregulation that inactivated SLC7A11, thus inducing ferroptosis [331]. These data further extend previous work in human breast cancer cells demonstrating that the JAK/STAT pathway, specifically STAT3 and STAT5 proteins, negatively regulate xCT expression [332].

4.5. NF-κB Pathway

Nuclear factor-κB (NF-κB) represents a family of transcription factors whose activity is induced by several cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), ROS/RNS, and harmful stimuli [333]. NF-κB controls crucial physiological processes, such as immunity [334], inflammatory response [335], proliferation, cell death, cancer, and nervous system function [336] by regulating various pro-inflammatory genes (cytokines and chemokines), immunoreceptors, cell adhesion molecules, and several cell cycle regulators [cyclin A, cyclin D1, or cyclin-dependent kinase 6 (CDK6)]. NF-κB activity has a crucial role in the development of malignant tumors. Its constitutive activation enhances cancer cell proliferation and promotes the inhibition of apoptosis and chemotherapy resistance in many cancer types [337].
The NF-κB family includes five proteins: Rel (cRel), p65 (RelA), RelB, p105, and p100. The last two proteins undergo proteolysis, producing the p50 (NFκB1), and p52 (NFκB2) subunits. Among these, p65, cRel, and RelB proteins contain an N-terminal Rel-homologous domain (RHD), necessary for DNA binding and dimerization with other family members, and a C-terminal transactivation domain (TAD), associated with transcriptional activation. p50 and p52 proteins have only an RHD, but not a TAD domain. The homo- and hetero-dimers of NF-κBs (i.e., RelB-p50, RelB-p52, and p50-p65) bind specific consensus sequences on target genes for transcription regulation [337]. Normally, NF-κB factors are in the cytoplasm where they associate with members of the inhibitor family (IκBα, β, and ε) that prevent nuclear translocation. The NF-κB/IκB association is impaired by phosphorylation of IκBs, mediated by a specific IKK (IκB kinase) complex, that causes IκB ubiquitination and subsequent proteasomal degradation, thus liberating NF-κB, which translocates into the nucleus to modulate downstream gene transcription [338].
NF-κB plays a dual role in ferroptosis events; in fact, it can either activate or inhibit ferroptosis, depending on the tissue/tumor type and on the specific stimulus. It can indeed modulate ferroptosis signaling by directly regulating several genes associated with iron accumulation and/or lipid peroxidation, as recently reviewed in [318]. Of note, a crosstalk between NF-κB/p65 and NRF2 was reported. In particular, NF-κB/p65 could counteract the NRF2/ARE cascade, which consequently may influence ferroptosis sensitivity. In fact, the knockdown of p65 by siRNA enhanced the NRF2-mediated activation of HO-1, GPX2, and NQO1 genes in hepatoma HepG2 cells, whereas co-transfection of HO-1(ARE), GPX2(ARE), or NQO1(ARE)-Luc reporters with either NF-κB, p65, or IKKβ expressing vectors inhibited ARE-driven expression [339]. In p65 overexpressing cells, co-immunoprecipitation experiments demonstrated that p65 inhibits NRF2 transcriptional activity through sequestering CBP (CREB binding protein), a common coactivator of p65 and NRF2. Because NRF2 cannot bind to CBP, its transcriptional activity was inhibited. Besides, p65 fosters the association of HDAC3 with either MafK or CBP, favoring recruitment of HDAC3 to ARE sequences and transcriptional repression [339].
A recent study by Xu et al. reported that the NF-κB pathway exerted a dominant protective function in ferroptosis occurring during ulcerative colitis (UC), a phenomenon linked to endoplasmic reticulum (ER) stress. In fact, a reduction of ER stress lowered ferroptosis in intestinal epithelial cells and ameliorated colitis. The authors noted that epithelial and mesenchymal cells in the colonic sections from UC patients presented elevated levels of activated p65 and mice models with targeted p65 deletion exacerbated colitis induced by dextran sulfate sodium. As expected, phosphorylation of p65 blunted ER stress-mediated ferroptosis, and this was mediated by the direct interaction of p65 with eIF2α [340]. In line with NF-κB’s ferroptotic protective function, another study reported that BAY 11-7085, a selective inhibitor of the NF-κB pathway, could induce this type of cell death through upregulating the NRF2-SLC7A11-HO-1 signaling pathway [27]. Detailed analyses in human breast cancer cells demonstrated that BAY mediated NRF2 nuclear translocation and increased HO-1 expression while cells deficient in SLC7A11 presented exacerbated ferroptosis. HO-1 also elicited ferrous iron accumulation, mitochondrial damage, and ER stress. Since NRF2 and SLC7A11 knockdown inhibited HO-1 induction, while HO-1 knockdown did not influence NRF2 and SLC7A11 levels, it seems that the hierarchy axis is NRF2-SLC7A11-HO-1 following BAY treatment [27].
Recently, dimethyl fumarate (DMF), an FDA-approved drug for multiple sclerosis that can protect against inflammation and pro-oxidant conditions, was reported to have a beneficial anti-ferroptosis role in cognitive diseases. These effects are mediated by the joint activities of DMF on the NRF2/ARE and NF-κB signaling pathways [341]. DMF treatment on the one hand decreased NF-κB-mediated pro-inflammatory cytokine expression and on the other hand, it activated NRF2/ARE signaling, which reduces features of ferroptosis, and increased HO-1, NQO1, and GPX4 expression [341]. It has been also described that NF-κB activation in glioblastoma cells by RSL3 treatment leads to an increase of lipid ROS and a reduction of anti-ferroptosis proteins such as GPX4, ATF4, and SLC7A11 [342]. Accordingly, NFκB inhibition with the BAY 11-7082 compound increased the expression of ferroptosis-related proteins, such as ATF4, SLC7A11, and HO-1, consequently lowering RSL3-induced ferroptosis. In addition, murine xenograft models demonstrated that RSL3-treated tumors were approximately one-quarter of the weight compared to control groups, but cotreatment with RSL3 and BAY 11-7082 resulted in a significant increase in tumor weight with respect to the only RSL3-treated tumors. Therefore, the NF-κB pathway could mediate ATF4 and SLC7A11 expression and in the condition of simultaneous GPX4 silencing could induce ferroptosis in glioblastoma cells; in fact, depletion of GPX4 alone is not sufficient to induce ferroptosis of glioblastoma cells and only GPX4 silencing causes a moderate cell proliferation blockage without altering SLC7A11 and ATF4 levels. Conversely, NF-κB pathway activation in GPX4 knocked-down glioma cells decreased ATF4 and SLC7A11 expression and significantly increased the occurrence of ferroptosis [342].
Many studies showed a negative effect of NF-κB on ferroptosis by exhausting cellular iron and preventing lipid peroxidation. Diffuse large B-cell lymphoma (DLBCL), the most frequent malignant lymphoma in adults, is characterized by constitutive NF-κB activation and consequently by a constitutive production of interleukin-6 (IL-6) and IL-10. Dimethyl fumarate (DMF) efficiently inhibited NF-κB signaling (and STAT3) in DLBCL cell lines, which showed a significant sensitivity toward DMF-induced ferroptosis, exhibiting massive lipid peroxidation and reduced GSH levels following the DMF treatment [343]. Gene expression profiling of DMF-treated HBL-1 cells, a human lymphoma cell line, revealed the downmodulation of several NF-κB target genes. Specifically, DMF treatment disrupted IKK complex activation by altering IκBα phosphorylation and consequently NF-κB nuclear translocation. Conversely, overexpression of the NF-κB member RelA decreased ferroptosis induced by DMF treatment, probably through the NF-κB-mediated induction of various antioxidant proteins, such as TRX, NQO1, HO-1, MnSOD, and FTH [343]. Wang et al. demonstrated that in hepatocellular carcinoma cells, NF-κB p65 hindered the in vitro and in vivo ferroptosis induced by aspirin. This effect was mediated by transcriptional activation of SLC7A11 through direct binding of NF-κB p65 to its promoter region. The authors proved that aspirin caused ferroptosis by inhibiting NF-κB p65-activated SLC7A11 transcription, whereas NF-κB p65 overexpression interfered with the aspirin-induced ferroptosis of hepatocellular carcinoma cells [344].
Myrislignan, a kind of lignan that inhibits NF-κB signaling in murine macrophage cells [345], significantly decreases the growth, migration, and invasion abilities of glioblastoma (GBM) cells. Zhou et al. demonstrated that myrislignan treatment in GBM cells inhibits the activation of the NF-κB signaling pathway through a reduction of IκB-α and p65 phosphorylation levels in U87 and U251 glioblastoma cells. By cotreatment with the myrislignan and ferroptosis inhibitor Fer-1, they showed that myrislignan-induced suppression of proliferation is caused by ferroptosis induction. Indeed, myrislignan decreased the levels of cystine and GSH and induced lipid peroxidation in GBM cells without altering iron pool levels. The molecular mechanism of myrislignan-induced ferroptosis involved a decrease in SLC7A11 expression, while NRF2, TFR1, and GPX4 levels remained unchanged. Further, knockdown of Slug/SNAI2, a transcription factor with a key role in TGFB signaling, enhanced the suppression of SLC7A11 level induced by myrislignan, suggesting that myrislignan regulated the ferroptosis of GBM cells via the Slug–SLC7A11 pathway. The effect of myrislignan on GBM was confirmed in vivo in the intracranial xenograft model; in particular, Western blot analysis and IHC staining demonstrated that expression of p-p65, Slug, and SLC7A11 declined in myrislignan-treated tumors. Thus, the authors determined that the NF-κB inhibitor myrislignan drives the ferroptosis of glioblastoma cells through Slug–SLC7A11 signaling [346].
NF-κB signaling could protect from ferroptosis by inducing the expression of lipocalin-2 (LCN2), a cytokine involved in iron homeostasis and inflammation [347]. Recently, Yao et al. reported that leukemia inhibitory factor receptor (LIFR) is frequently downregulated in liver cancer and its loss provokes liver tumorigenesis and confers resistance to drug-induced ferroptosis, as well as to erastin and RSL3 [348]. By RNA seq, the authors also demonstrated that LIFR loss in vivo and in vitro provoked upregulation of the iron-sequestering LCN2 and this was causally associated with induction of NF-κB signaling. Further analyses demonstrated that: (i) LIFR-knockout mouse liver progenitor cell lines (PHM) were resistant to ferroptosis, while LIFR overexpression sensitized PHM cells to ferroptosis inducers; (ii) the knockout of LIFR increased p65 phosphorylation in PHM and human liver cancer cell lines; conversely, LIFR overexpression reduced p65 phosphorylation, which was rescued by the knockdown of phosphatase SHP1; and (iii) knockdown of LIFR increased LCN2 levels, conferring resistance to erastin and sorafenib, which could be reversed by knockdown of LCN2. In conclusion, NF-κB-mediated LCN2 upregulation renders cells resistant to ferroptosis through the LIFR/SHP1 cascade in the liver.

4.6. p53 Pathway

The tumor suppressor p53 is a signal-activated sequence-specific DNA-binding protein, consisting of 393 amino acids with two tandem activation domains; a central DNA-binding domain; and a proline-rich domain, crucial for p53 interactions with proteins and for apoptosis regulation; an oligomerization domain necessary for activity; and a basic domain regulating the binding to responsive elements in the promoter regions of target genes [349]. The transcription cofactors CBP/p300 assist p53 in the activation of its target genes, including CDKN1A/p21 and murine double minute-2 (MDM2), through histone acetylation at promoter regions. Also, CBP/p300 can acetylate p53 itself, thus regulating DNA binding transactivation and protein stability [350]. Instead, MDM2, an E3 ubiquitin-protein ligase, is a p53 negative regulator, promoting its rapid degradation under conditions in which p53 is otherwise stabilized [351]. p53 is activated following cellular stress such as hypoxia, carcinogens, and oxidative stress, and coordinates the different cellular responses associated with DNA repair, apoptosis, ferroptosis, and energy metabolism. In particular, its activation leads to cell-cycle arrest favoring DNA repair or cell death induction by diverse pathways [66,352].
In recent years, an increasing number of works have highlighted that p53 is a critical factor in the regulation of ferroptosis. In particular, p53 has a dual role as it can promote or prevent ferroptosis, depending on the cell/tissue context and also on the type and the severity of stress, as well as damage upon stress exposure [66]. p53 activities in ferroptosis occur through transcriptional regulation of downstream genes and/or through diverse post-transcriptional modifications (PTMs) by which p53 activity are also regulated. p53 PTMs can be rapidly reversed, thus regulating its activity and function, and this represents a crucial event that markedly influences ferroptosis. For example, suppressor of cytokine signaling 1 (SOCS1) mediates p53 phosphorylation at Ser15, leading to ferroptosis-related downregulation of SLC7A11 and upregulation of spermidine/spermine N1-acetyltransferase 1 (SAT1) [352,353], while the attenuation of p53 phosphorylation at Ser46 in hepatocellular carcinoma HepG2, mediated by zinc finger protein 498 (ZNF498), lowered ROS production and GSL2 expression, and raised GSH production, with a consequent increase of cell survival and p53-mediated ferroptosis inhibition [354]. Also, CBP acetylates p53 (at residue K98 in the mouse and residue K101 in the human) without affecting the p53 DNA-binding capacity or transcriptional activity and this PTM retained p53’s ability to repress SLC7A11 expression and induce ferroptosis Instead, acetylation of p53 at K320 activates CDKN1A/p21 expression, hindering ferroptosis [64].
p53 also regulates several fundamental metabolic pathways involved in ferroptosis, providing control of GSH, glutamine, iron, and lipid peroxide levels. The molecular mechanism by which p53 mediates the metabolic regulation of ferroptosis was firstly reported by Le Jiang et al. [355], who identified SLC7A11 as a novel p53 target gene. The authors produced a tetracycline-controlled (tet-on) p53-inducible human non-small cell lung carcinoma H1299 cell line for microarray analysis, demonstrating that SLC7A11 mRNA and protein expression levels were strongly reduced upon p53 activation. On the contrary, SLC7A11 up-regulation was observed in p53-knockdown cells. p53 directly binds to a consensus sequence in the 5′ flanking region of the SLC7A11 gene and similar results were reproduced in other human cancer cell lines with wild-type p53 (H460 and MCF-7), while no effects were observed in p53-null cells (H1299 and SAOS-2). SLC7A11 overexpression counteracted erastin-induced ferroptosis and tumor growth suppression induced by p53 in xenograft tumor models. Also, mouse embryo fibroblasts (MEFs) derived from BAC transgenic mice overexpressing SLC7A11 (Slc7a11-BAC MEFs) treated with either ROS or erastin demonstrated that high levels of SLC7A11 reduced ferroptosis in wild-type MEFs. Therefore, p53 activation by decreasing SLC7A11-mediated cystine uptake can, in turn, limit the intracellular GSH concentration and increase ferroptosis cell death in the presence of ROS stress. Accordingly, p53 induced by nutlin-3 or by exposure to DNA damage stress (stimulating p53 function) sensitizes the cancer cells to ferroptosis [355].
p53 regulates iron levels through ferredoxin reductase (FDXR) and solute carrier family 25 member 28 (SLC25A28), which are two targets of p53, located in mitochondria. In the first case, Zhang et al. generated a Fdxr-deficient mouse model and found that Fdxr deficiency leads to embryonic lethality associated with iron overload with increased expression of IRP2 that in turn could block p53 mRNA translation, implying that FDXR may play a role in p53-dependent ferroptosis. That study proposed a model in which this FDXR–IRP2–p53 loop impacts iron metabolism [356]. Another paper reported that p53 regulates mitochondrial iron homeostasis in hepatic stellate cells by enhancing the activity of SLC25A28, which is involved in iron trafficking into mitochondria [357] The molecular mechanism involves bromodomain-containing protein 7 (BRD7)-mediated mitochondrial translocation of p53, which in turn directly interacts with SLC25A28, provoking iron overload and ETC hyperfunction, which consequently increases sensitivity to ferroptosis [357]. Another metabolic gene regulated by p53 and promoting ferroptosis is spermidine/spermine N1-acetyltransferase 1 (SAT1), a key enzyme of polyamine catabolism that was induced by nutlin-3 or doxorubicin treatment in cancer cell lines expressing wild-type p53 (U2OS, MCF7, and A375) but not in the p53-null cell line H1299 [358]. SAT1 transcription is directly upregulated by p53, which binds two sites on its promoter region. The injection of the SAT1 Tet-on H1299 cells into nude mice and induction of the SAT1 expression in xenograft mice showed a dramatic reduction of tumor growth. Treatment of SAT1 Tet-on cells with the ROS-inducing agent tert-butyl hydroperoxide (TBH) revealed that the combination of SAT1 over-expression and ROS treatment induced significant ferroptosis accompanied by up-regulation of prostaglandin-endoperoxide synthase 2 (COX2), identified as a potential molecular marker of ferroptosis [359], and an elevated lipid ROS level. Moreover, p53 activation by nutlin and ROS stress failed to induce ferroptosis in SAT1-knockout cells, indicating that SAT1 contributes to p53-mediated ferroptosis [358]. The authors identified the downstream effector of p53-induced SAT1 in the ALOX15 enzyme, firstly found in HT1080 [148]. Thus, p53 indirectly, by modulating the expression of ALOX15 via SAT1, affects phospholipid peroxidation in PUFA and initiates ferroptosis by an independent GSH and GPX4 axis [360]. Small molecules with the potential to be ferroptosis inducers in cancer cells are analogs sharing a common 4-cyclopentenyl-2-ethynylthiazole skeleton called CETZOLES [361]. Among these, CETZOLE1 blocks cystine uptake, leading to GSH loss, elevation of ROS, and lipid peroxidation [362]. Indeed, Nishanth Kuganesan et al. showed that p53−/− MEFs were less sensitive to CETZOLE 1 and to RSL3 than wild-type MEFs. Also, inducible systems in human adult fibroblasts TR9-7 cells for p53 levels displayed enhanced ferroptosis under CETZOLE1 treatment, and liproxstatin-1 decreased TR9-7 cell death provoked by CETZOLE1. Besides, the increased p53 in these cells caused a significantly elevation of membrane lipid peroxidation induced by CETZOLE 1 treatment. The authors also demonstrated that p21 can suppress CETEZOLE1-induced ferroptosis; therefore, p53 mediated ferroptosis in a p21-independent manner [362]. Indeed, CETZOLE1 does not induce ferroptosis in cells over-expressing p21 [362,363,364].
In some studies, p53 was proposed to inhibit ferroptosis in certain cell types, including HT1080 fibrosarcoma cells, that express wild-type p53. Stabilization of wild-type p53 by pretreatment of these cells with nutlin-3 makes them less responsive to system Xc- inhibition by erastin2 and this lower sensitivity requires p21 and preservation of the GSH content [365]. A similar effect was observed in the human osteosarcoma SJSa1 cell line, but not in human fetal lung fibroblasts IMR-90, where p53 stabilization does not affect erastin2-induced ferroptosis. Conversely, lung adenocarcinoma cell lines derived from p53 transactivation function-deficient mutant mice [366] do not suppress ferroptosis induced by erastin2 (an erastin analog), suggesting that p53 delays ferroptosis via transcriptional activation of its target genes, including p21 [365]. Of note, previous experiments have demonstrated that p21 could increase NRF2 levels by competing with Keap1-mediated NRF2 ubiquitination [367]. Therefore, p53 activation may also induce NRF2 activity via p21 increase to regulate an antioxidant gene expression program that preserves intracellular GSH [368].
p53 protective functions in ferroptosis can also be also independent of its transcriptional activity, as reported by Xie et al. in human colorectal cancer (CRC) cells [105]. In that paper, the sensitivity to erastin of wild-type p53 in CRC cells was restored following p53 silencing by transfection with small hairpin RNAs or by knockdown/pharmacological inhibition of p53, accompanied by an increase in erastin-induced SLC7A11 mRNA and protein expression levels. The authors found that p53 also inhibits erastin-induced ferroptosis by blocking dipeptidyl-peptidase-4 (DPP4) protease activity in a transcription-independent manner. In detail, DPP4 knockdown abrogates erastin-induced death of p53-knockdown CRC cells, indicating that DPP4 inactivation is required for ferroptosis in p53-deficient CRC cells. p53 downmodulation and real-time qPCR showed that p53 does not alter the mRNA expression level of DPP4; in the meantime, immunoblots and enzymatic activity assays revealed that p53 influences the subcellular localization and activity of DDP4. DDP4 can function as a serine protease at the plasma membrane, where it forms a complex with NOX1, contributing to lipid peroxidation and iron accumulation, and as a transcription cofactor in the nucleus. Thus, p53 favors the subcellular redistribution of DPP4 toward a nuclear enzymatically inactive pool. In conclusion, p53 limits ferroptosis by blocking DPP4 activity [105].
It is worth noting that many of the above TFs participating in the ferroptosis process can have common target genes, in some cases with opposite effects (Table 1), thus conceptualizing transcriptional pathways to and enabling a complex gene regulatory network impacting the redox system and the sensitivity profiling of ferroptosis.
Table 1. Common target genes regulated by different transcription factors. The green arrow indicates up-regulation and the red arrow indicates down-regulation. The presence of both arrows indicates that both effects have been demonstrated, depending on the different tissue and cellular contexts.

5. Conclusions

Ferroptosis is a newly discovered distinct type of regulated cell death associated with dysregulated iron homeostasis, ROS accumulation, and lipid peroxidation. Since its discovery in 2012, a large body of evidence has been gathered on the molecular mechanisms of ferroptosis and great efforts have been made to identify the effectors and potential inducers and inhibitors of this process. Furthermore, a link between ferroptosis and a variety of pathological processes and aging-related disorders has rapidly emerged, thus attracting extensive research interest in the potential therapeutic applications of ferroptosis induction or inhibition in several diseases. Nevertheless, research in this field is still in its early stages, and several questions need to be answered before considering ferroptotic-based treatments as an effective therapeutic option: (1) understanding the physiological functions of ferroptosis is still a challenging issue and needs to be clarified to evaluate possible preventive treatments, particularly in degenerative disorders; (2) it is evident that ferroptosis is a tissue- and cell-type dependent process; therefore, not all cancer types or even different clinical stages of the same type of cancer can be treated with the same ferroptosis-based cancer therapies; (3) further studies are required to clarify possible cross-talks between ferroptosis and other regulated cell death pathways that could contribute to more efficiently circumventing drug resistance in cancer.
Bearing this in mind, it is evident that a better understanding of the molecular mechanisms and the metabolic pathways controlling ferroptosis is of relevant importance. Given the broad function of transcription factors in antioxidant circuits, we envision that reprogramming of the intracellular antioxidant state needs to be considered as a novel therapeutic approach to the many human diseases that have ferroptosis as a common trait.

Author Contributions

Conceptualization, manuscript revision, R.F. and M.G.; literature search, manuscript draft preparation, visualization, C.P., S.T. and E.C. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Italian Association for Cancer Research (AIRC-IG-2021-ID-26111).

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sun, S.; Shen, J.; Jiang, J.; Wang, F.; Min, J. Targeting Ferroptosis Opens New Avenues for the Development of Novel Therapeutics. Signal Transduct. Target. Ther. 2023, 8, 372. [Google Scholar] [CrossRef]
  2. Wang, X.; Zhou, Y.; Min, J.; Wang, F. Zooming in and out of Ferroptosis in Human Disease. Front. Med. 2023, 17, 173–206. [Google Scholar] [CrossRef]
  3. Jiang, X.; Stockwell, B.R.; Conrad, M. Ferroptosis: Mechanisms, Biology and Role in Disease. Nat. Rev. Mol. Cell Biol 2021, 22, 266–282. [Google Scholar] [CrossRef] [PubMed]
  4. Lei, G.; Zhuang, L.; Gan, B. Targeting Ferroptosis as a Vulnerability in Cancer. Nat. Rev. Cancer 2022, 22, 381–396. [Google Scholar] [CrossRef] [PubMed]
  5. Chen, Z.; Wang, W.; Abdul Razak, S.R.; Han, T.; Ahmad, N.H.; Li, X. Ferroptosis as a Potential Target for Cancer Therapy. Cell Death Dis. 2023, 14, 460. [Google Scholar] [CrossRef]
  6. Xu, Y.; Zhao, J.; Zhao, Y.; Zhou, L.; Qiao, H.; Xu, Q.; Liu, Y. The Role of Ferroptosis in Neurodegenerative Diseases. Mol. Biol. Rep. 2023, 50, 1655–1661. [Google Scholar] [CrossRef] [PubMed]
  7. Coradduzza, D.; Congiargiu, A.; Chen, Z.; Zinellu, A.; Carru, C.; Medici, S. Ferroptosis and Senescence: A Systematic Review. Int. J. Mol. Sci. 2023, 24, 3658. [Google Scholar] [CrossRef]
  8. Chen, Z.; Jiang, J.; Fu, N.; Chen, L. Targetting Ferroptosis for Blood Cell-Related Diseases. J. Drug Target. 2022, 30, 244–258. [Google Scholar] [CrossRef] [PubMed]
  9. Yang, L.; Liu, Y.; Zhou, S.; Feng, Q.; Lu, Y.; Liu, D.; Liu, Z. Novel Insight into Ferroptosis in Kidney Diseases. Am. J. Nephrol. 2023, 54, 184–199. [Google Scholar] [CrossRef] [PubMed]
  10. Fang, X.; Ardehali, H.; Min, J.; Wang, F. The Molecular and Metabolic Landscape of Iron and Ferroptosis in Cardiovascular Disease. Nat. Rev. Cardiol. 2023, 20, 7–23. [Google Scholar] [CrossRef]
  11. Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; Skouta, R.; Zaitsev, E.M.; Gleason, C.E.; Patel, D.N.; Bauer, A.J.; Cantley, A.M.; Yang, W.S.; et al. Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death. Cell 2012, 149, 1060–1072. [Google Scholar] [CrossRef] [PubMed]
  12. Pope, L.E.; Dixon, S.J. Regulation of Ferroptosis by Lipid Metabolism. Trends Cell Biol. 2023, 33, 1077–1087. [Google Scholar] [CrossRef] [PubMed]
  13. Stockwell, B.R. Ferroptosis Turns 10: Emerging Mechanisms, Physiological Functions, and Therapeutic Applications. Cell 2022, 185, 2401–2421. [Google Scholar] [CrossRef] [PubMed]
  14. Dai, C.; Chen, X.; Li, J.; Comish, P.; Kang, R.; Tang, D. Transcription Factors in Ferroptotic Cell Death. Cancer Gene Ther. 2020, 27, 645–656. [Google Scholar] [CrossRef] [PubMed]
  15. Yan, R.; Lin, B.; Jin, W.; Tang, L.; Hu, S.; Cai, R. NRF2, a Superstar of Ferroptosis. Antioxidants 2023, 12, 1739. [Google Scholar] [CrossRef] [PubMed]
  16. Kist, M.; Vucic, D. Cell Death Pathways: Intricate Connections and Disease Implications. EMBO J. 2021, 40, e106700. [Google Scholar] [CrossRef]
  17. Land, W.G. Regulated Cell Death. In Damage-Associated Molecular Patterns in Human Diseases; Springer International Publishing: Cham, Switzerland, 2018; pp. 427–466. ISBN 978-3-319-78654-4. [Google Scholar]
  18. Di Meo, S.; Reed, T.T.; Venditti, P.; Victor, V.M. Role of ROS and RNS Sources in Physiological and Pathological Conditions. Oxidative Med. Cell. Longev. 2016, 2016, 1245049. [Google Scholar] [CrossRef]
  19. Metodiewa, D.; Kośka, C. Reactive Oxygen Species and Reactive Nitrogen Species: Relevance to Cyto(Neuro)Toxic Events and Neurologic Disorders. An Overview. Neurotox. Res. 2000, 1, 197–233. [Google Scholar] [CrossRef]
  20. Bayır, H.; Anthonymuthu, T.S.; Tyurina, Y.Y.; Patel, S.J.; Amoscato, A.A.; Lamade, A.M.; Yang, Q.; Vladimirov, G.K.; Philpott, C.C.; Kagan, V.E. Achieving Life through Death: Redox Biology of Lipid Peroxidation in Ferroptosis. Cell Chem. Biol. 2020, 27, 387–408. [Google Scholar] [CrossRef]
  21. Torii, S.; Shintoku, R.; Kubota, C.; Yaegashi, M.; Torii, R.; Sasaki, M.; Suzuki, T.; Mori, M.; Yoshimoto, Y.; Takeuchi, T.; et al. An Essential Role for Functional Lysosomes in Ferroptosis of Cancer Cells. Biochem. J. 2016, 473, 769–777. [Google Scholar] [CrossRef]
  22. Armenta, D.A.; Laqtom, N.N.; Alchemy, G.; Dong, W.; Morrow, D.; Poltorack, C.D.; Nathanson, D.A.; Abu-Remalieh, M.; Dixon, S.J. Ferroptosis Inhibition by Lysosome-Dependent Catabolism of Extracellular Protein. Cell Chem. Biol. 2022, 29, 1588–1600.e7. [Google Scholar] [CrossRef]
  23. Sousa, L.; Oliveira, M.M.; Pessôa, M.T.C.; Barbosa, L.A. Iron Overload: Effects on Cellular Biochemistry. Clin. Chim. Acta 2020, 504, 180–189. [Google Scholar] [CrossRef] [PubMed]
  24. Yiannikourides, A.; Latunde-Dada, G.O. A Short Review of Iron Metabolism and Pathophysiology of Iron Disorders. Medicines 2019, 6, 85. [Google Scholar] [CrossRef] [PubMed]
  25. Lanceta, L.; Li, C.; Choi, A.M.; Eaton, J.W. Haem Oxygenase-1 Overexpression Alters Intracellular Iron Distribution. Biochem. J. 2013, 449, 189–194. [Google Scholar] [CrossRef]
  26. Kwon, M.-Y.; Park, E.; Lee, S.-J.; Chung, S.W. Heme Oxygenase-1 Accelerates Erastin-Induced Ferroptotic Cell Death. Oncotarget 2015, 6, 24393–24403. [Google Scholar] [CrossRef]
  27. Chang, L.-C.; Chiang, S.-K.; Chen, S.-E.; Yu, Y.-L.; Chou, R.-H.; Chang, W.-C. Heme Oxygenase-1 Mediates BAY 11-7085 Induced Ferroptosis. Cancer Lett. 2018, 416, 124–137. [Google Scholar] [CrossRef]
  28. Hassannia, B.; Wiernicki, B.; Ingold, I.; Qu, F.; Van Herck, S.; Tyurina, Y.Y.; Bayır, H.; Abhari, B.A.; Angeli, J.P.F.; Choi, S.M.; et al. Nano-Targeted Induction of Dual Ferroptotic Mechanisms Eradicates High-Risk Neuroblastoma. J. Clin. Investig. 2018, 128, 3341–3355. [Google Scholar] [CrossRef]
  29. Zhou, B.; Liu, J.; Kang, R.; Klionsky, D.J.; Kroemer, G.; Tang, D. Ferroptosis Is a Type of Autophagy-Dependent Cell Death. Semin. Cancer Biol. 2020, 66, 89–100. [Google Scholar] [CrossRef] [PubMed]
  30. Yang, W.S.; Stockwell, B.R. Synthetic Lethal Screening Identifies Compounds Activating Iron-Dependent, Nonapoptotic Cell Death in Oncogenic-RAS-Harboring Cancer Cells. Chem. Biol. 2008, 15, 234–245. [Google Scholar] [CrossRef]
  31. Chen, X.; Yu, C.; Kang, R.; Tang, D. Iron Metabolism in Ferroptosis. Front. Cell Dev. Biol. 2020, 8, 590226. [Google Scholar] [CrossRef]
  32. Tang, D.; Chen, X.; Kang, R.; Kroemer, G. Ferroptosis: Molecular Mechanisms and Health Implications. Cell Res. 2021, 31, 107–125. [Google Scholar] [CrossRef] [PubMed]
  33. Galaris, D.; Barbouti, A.; Pantopoulos, K. Iron Homeostasis and Oxidative Stress: An Intimate Relationship. Biochim. Biophys. Acta Mol. Cell Res. 2019, 1866, 118535. [Google Scholar] [CrossRef] [PubMed]
  34. Su, L.-J.; Zhang, J.-H.; Gomez, H.; Murugan, R.; Hong, X.; Xu, D.; Jiang, F.; Peng, Z.-Y. Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis. Oxid. Med. Cell. Longev. 2019, 2019, 5080843. [Google Scholar] [CrossRef]
  35. Shah, R.; Shchepinov, M.S.; Pratt, D.A. Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis. ACS Cent. Sci. 2018, 4, 387–396. [Google Scholar] [CrossRef] [PubMed]
  36. Zou, Y.; Li, H.; Graham, E.T.; Deik, A.A.; Eaton, J.K.; Wang, W.; Sandoval-Gomez, G.; Clish, C.B.; Doench, J.G.; Schreiber, S.L. Cytochrome P450 Oxidoreductase Contributes to Phospholipid Peroxidation in Ferroptosis. Nat. Chem. Biol. 2020, 16, 302–309. [Google Scholar] [CrossRef]
  37. Carlsen, C.U.; Møller, J.K.S.; Skibsted, L.H. Heme-Iron in Lipid Oxidation. Coord. Chem. Rev. 2005, 249, 485–498. [Google Scholar] [CrossRef]
  38. Hajeyah, A.A.; Griffiths, W.J.; Wang, Y.; Finch, A.J.; O’Donnell, V.B. The Biosynthesis of Enzymatically Oxidized Lipids. Front. Endocrinol. 2020, 11, 591819. [Google Scholar] [CrossRef]
  39. Lee, J.-Y.; Kim, W.K.; Bae, K.-H.; Lee, S.C.; Lee, E.-W. Lipid Metabolism and Ferroptosis. Biology 2021, 10, 184. [Google Scholar] [CrossRef]
  40. Wu, P.; Zhang, X.; Duan, D.; Zhao, L. Organelle-Specific Mechanisms in Crosstalk between Apoptosis and Ferroptosis. Oxidative Med. Cell. Longev. 2023, 2023, 3400147. [Google Scholar] [CrossRef]
  41. Mortensen, M.S.; Ruiz, J.; Watts, J.L. Polyunsaturated Fatty Acids Drive Lipid Peroxidation during Ferroptosis. Cells 2023, 12, 804. [Google Scholar] [CrossRef]
  42. Zhang, X.; Ning, X.; He, X.; Sun, X.; Yu, X.; Cheng, Y.; Yu, R.-Q.; Wu, Y. Fatty Acid Composition Analyses of Commercially Important Fish Species from the Pearl River Estuary, China. PLoS ONE 2020, 15, e0228276. [Google Scholar] [CrossRef] [PubMed]
  43. Kim, J.W.; Lee, J.-Y.; Oh, M.; Lee, E.-W. An Integrated View of Lipid Metabolism in Ferroptosis Revisited via Lipidomic Analysis. Exp. Mol. Med. 2023, 55, 1620–1631. [Google Scholar] [CrossRef] [PubMed]
  44. Doll, S.; Conrad, M. Iron and Ferroptosis: A Still Ill-defined Liaison. IUBMB Life 2017, 69, 423–434. [Google Scholar] [CrossRef] [PubMed]
  45. Liu, Y.; Lu, S.; Wu, L.-L.; Yang, L.; Yang, L.; Wang, J. The Diversified Role of Mitochondria in Ferroptosis in Cancer. Cell Death Dis. 2023, 14, 519. [Google Scholar] [CrossRef] [PubMed]
  46. Gan, B. Mitochondrial Regulation of Ferroptosis. J. Cell Biol. 2021, 220, e202105043. [Google Scholar] [CrossRef]
  47. Kagan, V.E.; Tyurina, Y.Y.; Sun, W.Y.; Vlasova, I.I.; Dar, H.; Tyurin, V.A.; Amoscato, A.A.; Mallampalli, R.; Van Der Wel, P.C.A.; He, R.R.; et al. Redox Phospholipidomics of Enzymatically Generated Oxygenated Phospholipids as Specific Signals of Programmed Cell Death. Free Radic. Biol. Med. 2020, 147, 231–241. [Google Scholar] [CrossRef]
  48. Dixon, S.J.; Patel, D.N.; Welsch, M.; Skouta, R.; Lee, E.D.; Hayano, M.; Thomas, A.G.; Gleason, C.E.; Tatonetti, N.P.; Slusher, B.S.; et al. Pharmacological Inhibition of Cystine-Glutamate Exchange Induces Endoplasmic Reticulum Stress and Ferroptosis. eLife 2014, 3, e02523. [Google Scholar] [CrossRef]
  49. Gaschler, M.M.; Hu, F.; Feng, H.; Linkermann, A.; Min, W.; Stockwell, B.R. Determination of the Subcellular Localization and Mechanism of Action of Ferrostatins in Suppressing Ferroptosis. ACS Chem. Biol. 2018, 13, 1013–1020. [Google Scholar] [CrossRef]
  50. von Krusenstiern, A.N.; Robson, R.N.; Qian, N.; Qiu, B.; Hu, F.; Reznik, E.; Smith, N.; Zandkarimi, F.; Estes, V.M.; Dupont, M.; et al. Identification of Essential Sites of Lipid Peroxidation in Ferroptosis. Nat. Chem. Biol. 2023, 19, 719–730. [Google Scholar] [CrossRef]
  51. Stockwell, B.R.; Jiang, X.; Gu, W. Emerging Mechanisms and Disease Relevance of Ferroptosis. Trends Cell Biol. 2020, 30, 478–490. [Google Scholar] [CrossRef] [PubMed]
  52. Lettieri-Barbato, D.; Aquilano, K.; Punziano, C.; Minopoli, G.; Faraonio, R. MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Redox Control of Cell Senescence. Antioxidants 2022, 11, 480. [Google Scholar] [CrossRef] [PubMed]
  53. Maldonado, E.; Morales-Pison, S.; Urbina, F.; Solari, A. Aging Hallmarks and the Role of Oxidative Stress. Antioxidants 2023, 12, 651. [Google Scholar] [CrossRef]
  54. Li, Z.; Zhang, Z.; Ren, Y.; Wang, Y.; Fang, J.; Yue, H.; Ma, S.; Guan, F. Aging and Age-related Diseases: From Mechanisms to Therapeutic Strategies. Biogerontology 2021, 22, 165–187. [Google Scholar] [CrossRef] [PubMed]
  55. Zeidan, R.S.; Han, S.M.; Leeuwenburgh, C.; Xiao, R. Iron Homeostasis and Organismal Aging. Ageing Res. Rev. 2021, 72, 101510. [Google Scholar] [CrossRef]
  56. Mazhar, M.; Din, A.U.; Ali, H.; Yang, G.; Ren, W.; Wang, L.; Fan, X.; Yang, S. Implication of Ferroptosis in Aging. Cell Death Discov. 2021, 7, 149. [Google Scholar] [CrossRef] [PubMed]
  57. Luo, L.; Wang, H.; Tian, W.; Zeng, J.; Huang, Y.; Luo, H. Targeting Ferroptosis for Cancer Therapy: Iron Metabolism and Anticancer Immunity. Am. J. Cancer Res. 2021, 11, 5508–5525. [Google Scholar]
  58. Zhang, R.; Chen, J.; Wang, S.; Zhang, W.; Zheng, Q.; Cai, R. Ferroptosis in Cancer Progression. Cells 2023, 12, 1820. [Google Scholar] [CrossRef]
  59. Feng, S.; Tang, D.; Wang, Y.; Li, X.; Bao, H.; Tang, C.; Dong, X.; Li, X.; Yang, Q.; Yan, Y.; et al. The Mechanism of Ferroptosis and Its Related Diseases. Mol. Biomed. 2023, 4, 33. [Google Scholar] [CrossRef]
  60. Chen, H.; Wang, C.; Liu, Z.; He, X.; Tang, W.; He, L.; Feng, Y.; Liu, D.; Yin, Y.; Li, T. Ferroptosis and Its Multifaceted Role in Cancer: Mechanisms and Therapeutic Approach. Antioxidants 2022, 11, 1504. [Google Scholar] [CrossRef]
  61. Trombetti, S.; Cesaro, E.; Catapano, R.; Sessa, R.; Lo Bianco, A.; Izzo, P.; Grosso, M. Oxidative Stress and ROS-Mediated Signaling in Leukemia: Novel Promising Perspectives to Eradicate Chemoresistant Cells in Myeloid Leukemia. Int. J. Mol. Sci. 2021, 22, 2470. [Google Scholar] [CrossRef]
  62. Trombetti, S.; Iaccarino, N.; Riccio, P.; Sessa, R.; Catapano, R.; Salvatore, M.; Luka, S.; de Nicola, S.; Izzo, P.; Roperto, S.; et al. Over-Expressed GATA-1S, the Short Isoform of the Hematopoietic Transcriptional Factor GATA-1, Inhibits Ferroptosis in K562 Myeloid Leukemia Cells by Preventing Lipid Peroxidation. Antioxidants 2023, 12, 537. [Google Scholar] [CrossRef] [PubMed]
  63. Zhang, Q.; Fan, X.; Zhang, X.; Ju, S. Ferroptosis in Tumors and Its Relationship to Other Programmed Cell Death: Role of Non-Coding RNAs. J. Transl. Med. 2023, 21, 514. [Google Scholar] [CrossRef]
  64. Zhang, L.; Hou, N.; Chen, B.; Kan, C.; Han, F.; Zhang, J.; Sun, X. Post-Translational Modifications of P53 in Ferroptosis: Novel Pharmacological Targets for Cancer Therapy. Front. Pharmacol. 2022, 13, 908772. [Google Scholar] [CrossRef] [PubMed]
  65. Liu, Y.; Gu, W. P53 in Ferroptosis Regulation: The New Weapon for the Old Guardian. Cell Death Differ. 2022, 29, 895–910. [Google Scholar] [CrossRef] [PubMed]
  66. Xu, R.; Wang, W.; Zhang, W. Ferroptosis and the Bidirectional Regulatory Factor P53. Cell Death Discov. 2023, 9, 197. [Google Scholar] [CrossRef] [PubMed]
  67. Hayes, J.D.; Dinkova-Kostova, A.T.; Tew, K.D. Oxidative Stress in Cancer. Cancer Cell 2020, 38, 167–197. [Google Scholar] [CrossRef]
  68. Cai, H.; Ren, Y.; Chen, S.; Wang, Y.; Chu, L. Ferroptosis and Tumor Immunotherapy: A Promising Combination Therapy for Tumors. Front. Oncol. 2023, 13, 1119369. [Google Scholar] [CrossRef]
  69. Wang, S.; He, X.; Wu, Q.; Jiang, L.; Chen, L.; Yu, Y.; Zhang, P.; Huang, X.; Wang, J.; Ju, Z.; et al. Transferrin Receptor 1-Mediated Iron Uptake Plays an Essential Role in Hematopoiesis. Haematologica 2020, 105, 2071–2082. [Google Scholar] [CrossRef]
  70. Zhang, H.; Sun, C.; Sun, Q.; Li, Y.; Zhou, C.; Sun, C. Susceptibility of Acute Myeloid Leukemia Cells to Ferroptosis and Evasion Strategies. Front. Mol. Biosci. 2023, 10, 1275774. [Google Scholar] [CrossRef]
  71. Hole, P.S.; Darley, R.L.; Tonks, A. Do Reactive Oxygen Species Play a Role in Myeloid Leukemias? Blood 2011, 117, 5816–5826. [Google Scholar] [CrossRef]
  72. Udensi, U.K.; Tchounwou, P.B. Dual Effect of Oxidative Stress on Leukemia Cancer Induction and Treatment. J. Exp. Clin. Cancer Res. 2014, 33, 106. [Google Scholar] [CrossRef] [PubMed]
  73. Khoshtabiat, L.; Mahdavi, M.; Dehghan, G.; Rashidi, M.R. Oxidative Stress-Induced Apoptosis in Chronic Myelogenous Leukemia K562 Cells by an Active Compound from the Dithio- Carbamate Family. Asian Pac. J. Cancer Prev. 2016, 17, 4267–4273. [Google Scholar] [PubMed]
  74. Kaweme, N.M.; Zhou, S.; Changwe, G.J.; Zhou, F. The Significant Role of Redox System in Myeloid Leukemia: From Pathogenesis to Therapeutic Applications. Biomark. Res. 2020, 8, 63. [Google Scholar] [CrossRef]
  75. Weber, S.; Parmon, A.; Kurrle, N.; Schnütgen, F.; Serve, H. The Clinical Significance of Iron Overload and Iron Metabolism in Myelodysplastic Syndrome and Acute Myeloid Leukemia. Front. Immunol. 2020, 11, 627662. [Google Scholar] [CrossRef]
  76. Ma, W.; Wei, S.; Zhang, B.; Li, W. Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity. Front. Cell Dev. Biol. 2020, 8, 434. [Google Scholar] [CrossRef] [PubMed]
  77. Qiu, C.; Zhang, X.; Huang, B.; Wang, S.; Zhou, W.; Li, C.; Li, X.; Wang, J.; Yang, N. Disulfiram, a Ferroptosis Inducer, Triggers Lysosomal Membrane Permeabilization by Up-Regulating ROS in Glioblastoma. Onco Targets Ther. 2020, 13, 10631–10640. [Google Scholar] [CrossRef] [PubMed]
  78. Shirazi, L.F.; Bissett, J.; Romeo, F.; Mehta, J.L. Role of Inflammation in Heart Failure. Curr. Atheroscler. Rep. 2017, 19, 27. [Google Scholar] [CrossRef]
  79. Huang, S.; Frangogiannis, N.G. Anti-Inflammatory Therapies in Myocardial Infarction: Failures, Hopes and Challenges. Br. J. Pharmacol. 2018, 175, 1377–1400. [Google Scholar] [CrossRef]
  80. Luo, M.-Y.; Su, J.-H.; Gong, S.-X.; Liang, N.; Huang, W.-Q.; Chen, W.; Wang, A.-P.; Tian, Y. Ferroptosis: New Dawn for Overcoming the Cardio-Cerebrovascular Diseases. Front. Cell Dev. Biol. 2021, 9, 733908. [Google Scholar] [CrossRef]
  81. Liu, B.; Zhao, C.; Li, H.; Chen, X.; Ding, Y.; Xu, S. Puerarin Protects against Heart Failure Induced by Pressure Overload through Mitigation of Ferroptosis. Biochem. Biophys. Res. Commun. 2018, 497, 233–240. [Google Scholar] [CrossRef]
  82. Qin, Y.; Qiao, Y.; Wang, D.; Tang, C.; Yan, G. Ferritinophagy and Ferroptosis in Cardiovascular Disease: Mechanisms and Potential Applications. Biomed. Pharmacother. 2021, 141, 111872. [Google Scholar] [CrossRef] [PubMed]
  83. Wang, Y.; Wu, J. Ferroptosis: A New Strategy for Cardiovascular Disease. Front. Cardiovasc. Med. 2023, 10, 1241282. [Google Scholar] [CrossRef] [PubMed]
  84. Long, H.; Zhu, W.; Wei, L.; Zhao, J. Iron Homeostasis Imbalance and Ferroptosis in Brain Diseases. MedComm 2023, 4, e298. [Google Scholar] [CrossRef]
  85. Lin, K.-J.; Chen, S.-D.; Lin, K.-L.; Liou, C.-W.; Lan, M.-Y.; Chuang, Y.-C.; Wang, P.-W.; Lee, J.-J.; Wang, F.-S.; Lin, H.-Y.; et al. Iron Brain Menace: The Involvement of Ferroptosis in Parkinson Disease. Cells 2022, 11, 3829. [Google Scholar] [CrossRef]
  86. Ndayisaba, A.; Kaindlstorfer, C.; Wenning, G.K. Iron in Neurodegeneration-Cause or Consequence? Front. Neurosci. 2019, 13, 180. [Google Scholar] [CrossRef] [PubMed]
  87. Ji, Y.; Zheng, K.; Li, S.; Ren, C.; Shen, Y.; Tian, L.; Zhu, H.; Zhou, Z.; Jiang, Y. Insight into the Potential Role of Ferroptosis in Neurodegenerative Diseases. Front. Cell. Neurosci. 2022, 16, 1005182. [Google Scholar] [CrossRef]
  88. Reichert, C.O.; de Freitas, F.A.; Sampaio-Silva, J.; Rokita-Rosa, L.; de Lima Barros, P.; Levy, D.; Bydlowski, S.P. Ferroptosis Mechanisms Involved in Neurodegenerative Diseases. Int. J. Mol. Sci. 2020, 21, 8765. [Google Scholar] [CrossRef]
  89. Patanè, G.T.; Putaggio, S.; Tellone, E.; Barreca, D.; Ficarra, S.; Maffei, C.; Calderaro, A.; Laganà, G. Ferroptosis: Emerging Role in Diseases and Potential Implication of Bioactive Compounds. Int. J. Mol. Sci. 2023, 24, 17279. [Google Scholar] [CrossRef]
  90. Ding, X.; Gao, L.; Han, Z.; Eleuteri, S.; Shi, W.; Shen, Y.; Song, Z.; Su, M.; Yang, Q.; Qu, Y.; et al. Ferroptosis in Parkinson’s Disease: Molecular Mechanisms and Therapeutic Potential. Ageing Res. Rev. 2023, 91, 102077. [Google Scholar] [CrossRef]
  91. Zhou, Y.; Lin, W.; Rao, T.; Zheng, J.; Zhang, T.; Zhang, M.; Lin, Z. Ferroptosis and Its Potential Role in the Nervous System Diseases. JIR 2022, 15, 1555–1574. [Google Scholar] [CrossRef]
  92. Yu, Y.; Yan, Y.; Niu, F.; Wang, Y.; Chen, X.; Su, G.; Liu, Y.; Zhao, X.; Qian, L.; Liu, P.; et al. Ferroptosis: A Cell Death Connecting Oxidative Stress, Inflammation and Cardiovascular Diseases. Cell Death Discov. 2021, 7, 193. [Google Scholar] [CrossRef] [PubMed]
  93. Liu, M.; Kong, X.-Y.; Yao, Y.; Wang, X.-A.; Yang, W.; Wu, H.; Li, S.; Ding, J.-W.; Yang, J. The Critical Role and Molecular Mechanisms of Ferroptosis in Antioxidant Systems: A Narrative Review. Ann. Transl. Med. 2022, 10, 368. [Google Scholar] [CrossRef]
  94. Sies, H.; Jones, D.P. Reactive Oxygen Species (ROS) as Pleiotropic Physiological Signalling Agents. Nat. Rev. Mol. Cell Biol. 2020, 21, 363–383. [Google Scholar] [CrossRef] [PubMed]
  95. Sies, H. Hydrogen Peroxide as a Central Redox Signaling Molecule in Physiological Oxidative Stress: Oxidative Eustress. Redox Biol. 2017, 11, 613–619. [Google Scholar] [CrossRef]
  96. Tretter, V.; Hochreiter, B.; Zach, M.L.; Krenn, K.; Klein, K.U. Understanding Cellular Redox Homeostasis: A Challenge for Precision Medicine. Int. J. Mol. Sci. 2021, 23, 106. [Google Scholar] [CrossRef]
  97. Balaban, R.S.; Nemoto, S.; Finkel, T. Mitochondria, Oxidants, and Aging. Cell 2005, 120, 483–495. [Google Scholar] [CrossRef]
  98. Zhang, L.; Wang, X.; Cueto, R.; Effi, C.; Zhang, Y.; Tan, H.; Qin, X.; Ji, Y.; Yang, X.; Wang, H. Biochemical Basis and Metabolic Interplay of Redox Regulation. Redox Biol. 2019, 26, 101284. [Google Scholar] [CrossRef]
  99. Zhao, R.-Z.; Jiang, S.; Zhang, L.; Yu, Z.-B. Mitochondrial Electron Transport Chain, ROS Generation and Uncoupling (Review). Int. J. Mol. Med. 2019, 44, 3–15. [Google Scholar] [CrossRef]
  100. Kodama, R.; Kato, M.; Furuta, S.; Ueno, S.; Zhang, Y.; Matsuno, K.; Yabe-Nishimura, C.; Tanaka, E.; Kamata, T. ROS-Generating Oxidases Nox1 and Nox4 Contribute to Oncogenic Ras-Induced Premature Senescence. Genes Cells 2013, 18, 32–41. [Google Scholar] [CrossRef] [PubMed]
  101. Paulsen, C.E.; Carroll, K.S. Cysteine-Mediated Redox Signaling: Chemistry, Biology, and Tools for Discovery. Chem. Rev. 2013, 113, 4633–4679. [Google Scholar] [CrossRef] [PubMed]
  102. Sies, H.; Berndt, C.; Jones, D.P. Oxidative Stress. Annu. Rev. Biochem. 2017, 86, 715–748. [Google Scholar] [CrossRef] [PubMed]
  103. Skonieczna, M.; Hejmo, T.; Poterala-Hejmo, A.; Cieslar-Pobuda, A.; Buldak, R.J. NADPH Oxidases: Insights into Selected Functions and Mechanisms of Action in Cancer and Stem Cells. Oxidative Med. Cell. Longev. 2017, 2017, 9420539. [Google Scholar] [CrossRef] [PubMed]
  104. Park, M.W.; Cha, H.W.; Kim, J.; Kim, J.H.; Yang, H.; Yoon, S.; Boonpraman, N.; Yi, S.S.; Yoo, I.D.; Moon, J.-S. NOX4 Promotes Ferroptosis of Astrocytes by Oxidative Stress-Induced Lipid Peroxidation via the Impairment of Mitochondrial Metabolism in Alzheimer’s Diseases. Redox Biol. 2021, 41, 101947. [Google Scholar] [CrossRef] [PubMed]
  105. Xie, Y.; Zhu, S.; Song, X.; Sun, X.; Fan, Y.; Liu, J.; Zhong, M.; Yuan, H.; Zhang, L.; Billiar, T.R.; et al. The Tumor Suppressor P53 Limits Ferroptosis by Blocking DPP4 Activity. Cell Rep. 2017, 20, 1692–1704. [Google Scholar] [CrossRef]
  106. Yang, W.-H.; Ding, C.-K.C.; Sun, T.; Rupprecht, G.; Lin, C.-C.; Hsu, D.; Chi, J.-T. The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma. Cell Rep. 2019, 28, 2501–2508.e4. [Google Scholar] [CrossRef]
  107. Yang, W.-H.; Huang, Z.; Wu, J.; Ding, C.-K.C.; Murphy, S.K.; Chi, J.-T. A TAZ-ANGPTL4-NOX2 Axis Regulates Ferroptotic Cell Death and Chemoresistance in Epithelial Ovarian Cancer. Mol. Cancer Res. 2020, 18, 79–90. [Google Scholar] [CrossRef]
  108. Ju, H.-Q.; Lin, J.-F.; Tian, T.; Xie, D.; Xu, R.-H. NADPH Homeostasis in Cancer: Functions, Mechanisms and Therapeutic Implications. Signal Transduct. Target. Ther. 2020, 5, 231. [Google Scholar] [CrossRef]
  109. Gao, M.; Yi, J.; Zhu, J.; Minikes, A.M.; Monian, P.; Thompson, C.B.; Jiang, X. Role of Mitochondria in Ferroptosis. Mol. Cell 2019, 73, 354–363.e3. [Google Scholar] [CrossRef]
  110. Gao, M.; Monian, P.; Quadri, N.; Ramasamy, R.; Jiang, X. Glutaminolysis and Transferrin Regulate Ferroptosis. Mol. Cell 2015, 59, 298–308. [Google Scholar] [CrossRef]
  111. Suzuki, S.; Venkatesh, D.; Kanda, H.; Nakayama, A.; Hosokawa, H.; Lee, E.; Miki, T.; Stockwell, B.R.; Yokote, K.; Tanaka, T.; et al. GLS2 Is a Tumor Suppressor and a Regulator of Ferroptosis in Hepatocellular Carcinoma. Cancer Res. 2022, 82, 3209–3222. [Google Scholar] [CrossRef] [PubMed]
  112. Shin, D.; Lee, J.; You, J.H.; Kim, D.; Roh, J.-L. Dihydrolipoamide Dehydrogenase Regulates Cystine Deprivation-Induced Ferroptosis in Head and Neck Cancer. Redox Biol. 2020, 30, 101418. [Google Scholar] [CrossRef]
  113. Quinlan, C.L.; Goncalves, R.L.S.; Hey-Mogensen, M.; Yadava, N.; Bunik, V.I.; Brand, M.D. The 2-Oxoacid Dehydrogenase Complexes in Mitochondria Can Produce Superoxide/Hydrogen Peroxide at Much Higher Rates than Complex I. J. Biol. Chem. 2014, 289, 8312–8325. [Google Scholar] [CrossRef]
  114. Song, X.; Liu, J.; Kuang, F.; Chen, X.; Zeh, H.J.; Kang, R.; Kroemer, G.; Xie, Y.; Tang, D. PDK4 Dictates Metabolic Resistance to Ferroptosis by Suppressing Pyruvate Oxidation and Fatty Acid Synthesis. Cell Rep. 2021, 34, 108767. [Google Scholar] [CrossRef]
  115. Zorova, L.D.; Popkov, V.A.; Plotnikov, E.Y.; Silachev, D.N.; Pevzner, I.B.; Jankauskas, S.S.; Babenko, V.A.; Zorov, S.D.; Balakireva, A.V.; Juhaszova, M.; et al. Mitochondrial Membrane Potential. Anal. Biochem. 2018, 552, 50–59. [Google Scholar] [CrossRef] [PubMed]
  116. Atkinson, A.; Winge, D.R. Metal Acquisition and Availability in the Mitochondria. Chem. Rev. 2009, 109, 4708–4721. [Google Scholar] [CrossRef] [PubMed]
  117. Lipper, C.H.; Stofleth, J.T.; Bai, F.; Sohn, Y.-S.; Roy, S.; Mittler, R.; Nechushtai, R.; Onuchic, J.N.; Jennings, P.A. Redox-Dependent Gating of VDAC by mitoNEET. Proc. Natl. Acad. Sci. USA 2019, 116, 19924–19929. [Google Scholar] [CrossRef] [PubMed]
  118. Yagoda, N.; von Rechenberg, M.; Zaganjor, E.; Bauer, A.J.; Yang, W.S.; Fridman, D.J.; Wolpaw, A.J.; Smukste, I.; Peltier, J.M.; Boniface, J.J.; et al. RAS-RAF-MEK-Dependent Oxidative Cell Death Involving Voltage-Dependent Anion Channels. Nature 2007, 447, 864–868. [Google Scholar] [CrossRef] [PubMed]
  119. Mao, C.; Liu, X.; Zhang, Y.; Lei, G.; Yan, Y.; Lee, H.; Koppula, P.; Wu, S.; Zhuang, L.; Fang, B.; et al. DHODH-Mediated Ferroptosis Defence Is a Targetable Vulnerability in Cancer. Nature 2021, 593, 586–590. [Google Scholar] [CrossRef] [PubMed]
  120. Wu, S.; Mao, C.; Kondiparthi, L.; Poyurovsky, M.V.; Olszewski, K.; Gan, B. A Ferroptosis Defense Mechanism Mediated by Glycerol-3-Phosphate Dehydrogenase 2 in Mitochondria. Proc. Natl. Acad. Sci. USA 2022, 119, e2121987119. [Google Scholar] [CrossRef] [PubMed]
  121. Mittler, R.; Darash-Yahana, M.; Sohn, Y.S.; Bai, F.; Song, L.; Cabantchik, I.Z.; Jennings, P.A.; Onuchic, J.N.; Nechushtai, R. NEET Proteins: A New Link Between Iron Metabolism, Reactive Oxygen Species, and Cancer. Antioxid. Redox Signal. 2019, 30, 1083–1095. [Google Scholar] [CrossRef]
  122. Yuan, H.; Li, X.; Zhang, X.; Kang, R.; Tang, D. CISD1 Inhibits Ferroptosis by Protection against Mitochondrial Lipid Peroxidation. Biochem. Biophys. Res. Commun. 2016, 478, 838–844. [Google Scholar] [CrossRef]
  123. Bagheri, M.; Nair, R.R.; Singh, K.K.; Saini, D.K. ATM-ROS-iNOS Axis Regulates Nitric Oxide Mediated Cellular Senescence. Biochim. Biophys. Acta Mol. Cell Res. 2017, 1864, 177–190. [Google Scholar] [CrossRef]
  124. Pourbagher-Shahri, A.M.; Farkhondeh, T.; Talebi, M.; Kopustinskiene, D.M.; Samarghandian, S.; Bernatoniene, J. An Overview of NO Signaling Pathways in Aging. Molecules 2021, 26, 4533. [Google Scholar] [CrossRef] [PubMed]
  125. Wink, D.A.; Miranda, K.M.; Espey, M.G.; Pluta, R.M.; Hewett, S.J.; Colton, C.; Vitek, M.; Feelisch, M.; Grisham, M.B. Mechanisms of the Antioxidant Effects of Nitric Oxide. Antioxid. Redox Signal. 2001, 3, 203–213. [Google Scholar] [CrossRef]
  126. Radi, R. Peroxynitrite, a Stealthy Biological Oxidant. J. Biol. Chem. 2013, 288, 26464–26472. [Google Scholar] [CrossRef] [PubMed]
  127. White, C.R.; Brock, T.A.; Chang, L.Y.; Crapo, J.; Briscoe, P.; Ku, D.; Bradley, W.A.; Gianturco, S.H.; Gore, J.; Freeman, B.A. Superoxide and Peroxynitrite in Atherosclerosis. Proc. Natl. Acad. Sci. USA 1994, 91, 1044–1048. [Google Scholar] [CrossRef] [PubMed]
  128. Mastrogiovanni, M.; Trostchansky, A.; Rubbo, H. Fatty Acid Nitration in Human Low-Density Lipoprotein. Arch. Biochem. Biophys. 2020, 679, 108190. [Google Scholar] [CrossRef] [PubMed]
  129. Pacher, P.; Beckman, J.S.; Liaudet, L. Nitric Oxide and Peroxynitrite in Health and Disease. Physiol. Rev. 2007, 87, 315–424. [Google Scholar] [CrossRef] [PubMed]
  130. Conrad, M.; Pratt, D.A. The Chemical Basis of Ferroptosis. Nat. Chem. Biol. 2019, 15, 1137–1147. [Google Scholar] [CrossRef]
  131. Do, Q.; Zhang, R.; Hooper, G.; Xu, L. Differential Contributions of Distinct Free Radical Peroxidation Mechanisms to the Induction of Ferroptosis. JACS Au 2023, 3, 1100–1117. [Google Scholar] [CrossRef]
  132. Yin, H.; Xu, L.; Porter, N.A. Free Radical Lipid Peroxidation: Mechanisms and Analysis. Chem. Rev. 2011, 111, 5944–5972. [Google Scholar] [CrossRef]
  133. Ursini, F.; Maiorino, M. Lipid Peroxidation and Ferroptosis: The Role of GSH and GPx4. Free Radic. Biol. Med. 2020, 152, 175–185. [Google Scholar] [CrossRef]
  134. Ayala, A.; Muñoz, M.F.; Argüelles, S. Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal. Oxidative Med. Cell. Longev. 2014, 2014, 360438. [Google Scholar] [CrossRef] [PubMed]
  135. Liu, W.; Porter, N.A.; Schneider, C.; Brash, A.R.; Yin, H. Formation of 4-Hydroxynonenal from Cardiolipin Oxidation: Intramolecular Peroxyl Radical Addition and Decomposition. Free Radic. Biol. Med. 2011, 50, 166–178. [Google Scholar] [CrossRef]
  136. Riegman, M.; Sagie, L.; Galed, C.; Levin, T.; Steinberg, N.; Dixon, S.J.; Wiesner, U.; Bradbury, M.S.; Niethammer, P.; Zaritsky, A.; et al. Ferroptosis Occurs through an Osmotic Mechanism and Propagates Independently of Cell Rupture. Nat. Cell Biol. 2020, 22, 1042–1048. [Google Scholar] [CrossRef] [PubMed]
  137. Fujii, J.; Soma, Y.; Matsuda, Y. Biological Action of Singlet Molecular Oxygen from the Standpoint of Cell Signaling, Injury and Death. Molecules 2023, 28, 4085. [Google Scholar] [CrossRef]
  138. Onyango, A.N. Endogenous Generation of Singlet Oxygen and Ozone in Human and Animal Tissues: Mechanisms, Biological Significance, and Influence of Dietary Components. Oxidative Med. Cell. Longev. 2016, 2016, 2398573. [Google Scholar] [CrossRef]
  139. Murotomi, K.; Umeno, A.; Shichiri, M.; Tanito, M.; Yoshida, Y. Significance of Singlet Oxygen Molecule in Pathologies. Int. J. Mol. Sci. 2023, 24, 2739. [Google Scholar] [CrossRef] [PubMed]
  140. Davis, S.J.; Zhao, Y.; Yu, T.C.; Maytin, E.V.; Anand, S.; Hasan, T.; Pogue, B.W. Singlet Molecular Oxygen: From COIL Lasers to Photodynamic Cancer Therapy. J. Phys. Chem. B 2023, 127, 2289–2301. [Google Scholar] [CrossRef]
  141. Kuhn, H.; Banthiya, S.; van Leyen, K. Mammalian Lipoxygenases and Their Biological Relevance. Biochim. Biophys. Acta 2015, 1851, 308–330. [Google Scholar] [CrossRef]
  142. Schneider, C.; Pratt, D.A.; Porter, N.A.; Brash, A.R. Control of Oxygenation in Lipoxygenase and Cyclooxygenase Catalysis. Chem. Biol. 2007, 14, 473–488. [Google Scholar] [CrossRef]
  143. Pratt, D.A. Targeting Lipoxygenases to Suppress Ferroptotic Cell Death. Proc. Natl. Acad. Sci. USA 2023, 120, e2309317120. [Google Scholar] [CrossRef]
  144. Kagan, V.E.; Mao, G.; Qu, F.; Angeli, J.P.F.; Doll, S.; Croix, C.S.; Dar, H.H.; Liu, B.; Tyurin, V.A.; Ritov, V.B.; et al. Oxidized Arachidonic and Adrenic PEs Navigate Cells to Ferroptosis. Nat. Chem. Biol. 2017, 13, 81–90. [Google Scholar] [CrossRef]
  145. Mikulska-Ruminska, K.; Anthonymuthu, T.S.; Levkina, A.; Shrivastava, I.H.; Kapralov, A.A.; Bayır, H.; Kagan, V.E.; Bahar, I. NO● Represses the Oxygenation of Arachidonoyl PE by 15LOX/PEBP1: Mechanism and Role in Ferroptosis. Int. J. Mol. Sci. 2021, 22, 5253. [Google Scholar] [CrossRef] [PubMed]
  146. Yang, W.S.; Kim, K.J.; Gaschler, M.M.; Patel, M.; Shchepinov, M.S.; Stockwell, B.R. Peroxidation of Polyunsaturated Fatty Acids by Lipoxygenases Drives Ferroptosis. Proc. Natl. Acad. Sci. USA 2016, 113, E4966–E4975. [Google Scholar] [CrossRef] [PubMed]
  147. Magtanong, L.; Ko, P.-J.; To, M.; Cao, J.Y.; Forcina, G.C.; Tarangelo, A.; Ward, C.C.; Cho, K.; Patti, G.J.; Nomura, D.K.; et al. Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State. Cell Chem. Biol. 2019, 26, 420–432.e9. [Google Scholar] [CrossRef] [PubMed]
  148. Shintoku, R.; Takigawa, Y.; Yamada, K.; Kubota, C.; Yoshimoto, Y.; Takeuchi, T.; Koshiishi, I.; Torii, S. Lipoxygenase-Mediated Generation of Lipid Peroxides Enhances Ferroptosis Induced by Erastin and RSL3. Cancer Sci. 2017, 108, 2187–2194. [Google Scholar] [CrossRef] [PubMed]
  149. Chu, B.; Kon, N.; Chen, D.; Li, T.; Liu, T.; Jiang, L.; Song, S.; Tavana, O.; Gu, W. ALOX12 Is Required for P53-Mediated Tumour Suppression through a Distinct Ferroptosis Pathway. Nat. Cell Biol. 2019, 21, 579–591. [Google Scholar] [CrossRef] [PubMed]
  150. Wenzel, S.E.; Tyurina, Y.Y.; Zhao, J.; St Croix, C.M.; Dar, H.H.; Mao, G.; Tyurin, V.A.; Anthonymuthu, T.S.; Kapralov, A.A.; Amoscato, A.A.; et al. PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell 2017, 171, 628–641.e26. [Google Scholar] [CrossRef] [PubMed]
  151. Dar, H.H.; Mikulska-Ruminska, K.; Tyurina, Y.Y.; Luci, D.K.; Yasgar, A.; Samovich, S.N.; Kapralov, A.A.; Souryavong, A.B.; Tyurin, V.A.; Amoscato, A.A.; et al. Discovering Selective Antiferroptotic Inhibitors of the 15LOX/PEBP1 Complex Noninterfering with Biosynthesis of Lipid Mediators. Proc. Natl. Acad. Sci. USA 2023, 120, e2218896120. [Google Scholar] [CrossRef] [PubMed]
  152. Jia, B.; Li, J.; Song, Y.; Luo, C. ACSL4-Mediated Ferroptosis and Its Potential Role in Central Nervous System Diseases and Injuries. Int. J. Mol. Sci. 2023, 24, 10021. [Google Scholar] [CrossRef]
  153. Lagrost, L.; Masson, D. The Expanding Role of Lyso-Phosphatidylcholine Acyltransferase-3 (LPCAT3), a Phospholipid Remodeling Enzyme, in Health and Disease. Curr. Opin. Lipidol. 2022, 33, 193–198. [Google Scholar] [CrossRef]
  154. Doll, S.; Proneth, B.; Tyurina, Y.Y.; Panzilius, E.; Kobayashi, S.; Ingold, I.; Irmler, M.; Beckers, J.; Aichler, M.; Walch, A.; et al. ACSL4 Dictates Ferroptosis Sensitivity by Shaping Cellular Lipid Composition. Nat. Chem. Biol. 2017, 13, 91–98. [Google Scholar] [CrossRef] [PubMed]
  155. Dixon, S.J.; Winter, G.E.; Musavi, L.S.; Lee, E.D.; Snijder, B.; Rebsamen, M.; Superti-Furga, G.; Stockwell, B.R. Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death. ACS Chem. Biol. 2015, 10, 1604–1609. [Google Scholar] [CrossRef] [PubMed]
  156. Yan, B.; Ai, Y.; Sun, Q.; Ma, Y.; Cao, Y.; Wang, J.; Zhang, Z.; Wang, X. Membrane Damage during Ferroptosis Is Caused by Oxidation of Phospholipids Catalyzed by the Oxidoreductases POR and CYB5R1. Mol. Cell 2021, 81, 355–369.e10. [Google Scholar] [CrossRef]
  157. Reed, A.; Ichu, T.-A.; Milosevich, N.; Melillo, B.; Schafroth, M.A.; Otsuka, Y.; Scampavia, L.; Spicer, T.P.; Cravatt, B.F. LPCAT3 Inhibitors Remodel the Polyunsaturated Phospholipid Content of Human Cells and Protect from Ferroptosis. ACS Chem. Biol. 2022, 17, 1607–1618. [Google Scholar] [CrossRef]
  158. Cui, J.; Wang, Y.; Tian, X.; Miao, Y.; Ma, L.; Zhang, C.; Xu, X.; Wang, J.; Fang, W.; Zhang, X. LPCAT3 Is Transcriptionally Regulated by YAP/ZEB/EP300 and Collaborates with ACSL4 and YAP to Determine Ferroptosis Sensitivity. Antioxid. Redox Signal. 2023, 39, 491–511. [Google Scholar] [CrossRef]
  159. Yang, Y.; Zhu, T.; Wang, X.; Xiong, F.; Hu, Z.; Qiao, X.; Yuan, X.; Wang, D. ACSL3 and ACSL4, Distinct Roles in Ferroptosis and Cancers. Cancers 2022, 14, 5896. [Google Scholar] [CrossRef] [PubMed]
  160. Liang, D.; Feng, Y.; Zandkarimi, F.; Wang, H.; Zhang, Z.; Kim, J.; Cai, Y.; Gu, W.; Stockwell, B.R.; Jiang, X. Ferroptosis Surveillance Independent of GPX4 and Differentially Regulated by Sex Hormones. Cell 2023, 186, 2748–2764.e22. [Google Scholar] [CrossRef]
  161. Pandey, A.V.; Flück, C.E. NADPH P450 Oxidoreductase: Structure, Function, and Pathology of Diseases. Pharmacol. Ther. 2013, 138, 229–254. [Google Scholar] [CrossRef]
  162. Dean, J.M.; Lodhi, I.J. Structural and Functional Roles of Ether Lipids. Protein Cell 2018, 9, 196–206. [Google Scholar] [CrossRef] [PubMed]
  163. Tang, D.; Kroemer, G. Peroxisome: The New Player in Ferroptosis. Signal Transduct. Target. Ther. 2020, 5, 273. [Google Scholar] [CrossRef] [PubMed]
  164. Lee, H.; Zhuang, L.; Gan, B. Ether Phospholipids Govern Ferroptosis. J. Genet. Genom. 2021, 48, 517–519. [Google Scholar] [CrossRef] [PubMed]
  165. Zou, Y.; Henry, W.S.; Ricq, E.L.; Graham, E.T.; Phadnis, V.V.; Maretich, P.; Paradkar, S.; Boehnke, N.; Deik, A.A.; Reinhardt, F.; et al. Plasticity of Ether Lipids Promotes Ferroptosis Susceptibility and Evasion. Nature 2020, 585, 603–608. [Google Scholar] [CrossRef] [PubMed]
  166. Cui, W.; Liu, D.; Gu, W.; Chu, B. Peroxisome-Driven Ether-Linked Phospholipids Biosynthesis Is Essential for Ferroptosis. Cell Death Differ. 2021, 28, 2536–2551. [Google Scholar] [CrossRef] [PubMed]
  167. Marsh, K.G.; Arrieta, A.; Thuerauf, D.J.; Blackwood, E.A.; MacDonnell, L.; Glembotski, C.C. The Peroxisomal Enzyme, FAR1, Is Induced during ER Stress in an ATF6-Dependent Manner in Cardiac Myocytes. Am. J. Physiol. Heart Circ. Physiol. 2021, 320, H1813–H1821. [Google Scholar] [CrossRef]
  168. Ahmadinejad, F.; Geir Møller, S.; Hashemzadeh-Chaleshtori, M.; Bidkhori, G.; Jami, M.-S. Molecular Mechanisms behind Free Radical Scavengers Function against Oxidative Stress. Antioxidants 2017, 6, 51. [Google Scholar] [CrossRef]
  169. Wang, Y.; Branicky, R.; Noë, A.; Hekimi, S. Superoxide Dismutases: Dual Roles in Controlling ROS Damage and Regulating ROS Signaling. J. Cell Biol. 2018, 217, 1915–1928. [Google Scholar] [CrossRef]
  170. Amos, A.; Jiang, N.; Zong, D.; Gu, J.; Zhou, J.; Yin, L.; He, X.; Xu, Y.; Wu, L. Depletion of SOD2 Enhances Nasopharyngeal Carcinoma Cell Radiosensitivity via Ferroptosis Induction Modulated by DHODH Inhibition. BMC Cancer 2023, 23, 117. [Google Scholar] [CrossRef]
  171. Boukalova, S.; Hubackova, S.; Milosevic, M.; Ezrova, Z.; Neuzil, J.; Rohlena, J. Dihydroorotate Dehydrogenase in Oxidative Phosphorylation and Cancer. Biochim. Biophys. Acta Mol. Basis Dis. 2020, 1866, 165759. [Google Scholar] [CrossRef]
  172. Riccio, P.; Sessa, R.; de Nicola, S.; Petruzziello, F.; Trombetti, S.; Menna, G.; Pepe, G.; Maddalena, P.; Izzo, P.; Grosso, M. GATA-1 Isoforms Differently Contribute to the Production and Compartmentation of Reactive Oxygen Species in the Myeloid Leukemia Cell Line K562. J. Cell. Physiol. 2019, 234, 20829–20846. [Google Scholar] [CrossRef] [PubMed]
  173. Trombetti, S.; Sessa, R.; Catapano, R.; Rinaldi, L.; Lo Bianco, A.; Feliciello, A.; Izzo, P.; Grosso, M. Exploring the Leukemogenic Potential of GATA-1S, the Shorter Isoform of GATA-1: Novel Insights into Mechanisms Hampering Respiratory Chain Complex II Activity and Limiting Oxidative Phosphorylation Efficiency. Antioxidants 2021, 10, 1603. [Google Scholar] [CrossRef] [PubMed]
  174. Zeida, A.; Trujillo, M.; Ferrer-Sueta, G.; Denicola, A.; Estrin, D.A.; Radi, R. Catalysis of Peroxide Reduction by Fast Reacting Protein Thiols. Chem. Rev. 2019, 119, 10829–10855. [Google Scholar] [CrossRef] [PubMed]
  175. Nandi, A.; Yan, L.-J.; Jana, C.K.; Das, N. Role of Catalase in Oxidative Stress- and Age-Associated Degenerative Diseases. Oxidative Med. Cell. Longev. 2019, 2019, 9613090. [Google Scholar] [CrossRef]
  176. Hwang, J.S.; Kim, E.; Lee, H.G.; Lee, W.J.; Won, J.P.; Hur, J.; Fujii, J.; Seo, H.G. Peroxisome Proliferator-Activated Receptor δ Rescues xCT-Deficient Cells from Ferroptosis by Targeting Peroxisomes. Biomed. Pharmacother. 2021, 143, 112223. [Google Scholar] [CrossRef]
  177. Kanner, J.; Harel, S.; Granit, R. Nitric Oxide, an Inhibitor of Lipid Oxidation by Lipoxygenase, Cyclooxygenase and Hemoglobin. Lipids 1992, 27, 46–49. [Google Scholar] [CrossRef]
  178. Kapralov, A.A.; Yang, Q.; Dar, H.H.; Tyurina, Y.Y.; Anthonymuthu, T.S.; Kim, R.; St Croix, C.M.; Mikulska-Ruminska, K.; Liu, B.; Shrivastava, I.H.; et al. Redox Lipid Reprogramming Commands Susceptibility of Macrophages and Microglia to Ferroptotic Death. Nat. Chem. Biol. 2020, 16, 278–290. [Google Scholar] [CrossRef]
  179. Homma, T.; Kobayashi, S.; Conrad, M.; Konno, H.; Yokoyama, C.; Fujii, J. Nitric Oxide Protects against Ferroptosis by Aborting the Lipid Peroxidation Chain Reaction. Nitric Oxide 2021, 115, 34–43. [Google Scholar] [CrossRef]
  180. Astudillo, A.M.; Balboa, M.A.; Balsinde, J. Compartmentalized Regulation of Lipid Signaling in Oxidative Stress and Inflammation: Plasmalogens, Oxidized Lipids and Ferroptosis as New Paradigms of Bioactive Lipid Research. Prog. Lipid Res. 2023, 89, 101207. [Google Scholar] [CrossRef]
  181. Morgan, N.V.; Westaway, S.K.; Morton, J.E.V.; Gregory, A.; Gissen, P.; Sonek, S.; Cangul, H.; Coryell, J.; Canham, N.; Nardocci, N.; et al. PLA2G6, Encoding a Phospholipase A2, Is Mutated in Neurodegenerative Disorders with High Brain Iron. Nat. Genet. 2006, 38, 752–754. [Google Scholar] [CrossRef]
  182. Paisan-Ruiz, C.; Bhatia, K.P.; Li, A.; Hernandez, D.; Davis, M.; Wood, N.W.; Hardy, J.; Houlden, H.; Singleton, A.; Schneider, S.A. Characterization of PLA2G6 as a Locus for Dystonia-Parkinsonism. Ann. Neurol. 2009, 65, 19–23. [Google Scholar] [CrossRef]
  183. Astudillo, A.M.; Balboa, M.A.; Balsinde, J. Selectivity of Phospholipid Hydrolysis by Phospholipase A2 Enzymes in Activated Cells Leading to Polyunsaturated Fatty Acid Mobilization. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2019, 1864, 772–783. [Google Scholar] [CrossRef] [PubMed]
  184. Chen, D.; Chu, B.; Yang, X.; Liu, Z.; Jin, Y.; Kon, N.; Rabadan, R.; Jiang, X.; Stockwell, B.R.; Gu, W. iPLA2β-Mediated Lipid Detoxification Controls P53-Driven Ferroptosis Independent of GPX4. Nat. Commun. 2021, 12, 3644. [Google Scholar] [CrossRef]
  185. Beharier, O.; Tyurin, V.A.; Goff, J.P.; Guerrero-Santoro, J.; Kajiwara, K.; Chu, T.; Tyurina, Y.Y.; St Croix, C.M.; Wallace, C.T.; Parry, S.; et al. PLA2G6 Guards Placental Trophoblasts against Ferroptotic Injury. Proc. Natl. Acad. Sci. USA 2020, 117, 27319–27328. [Google Scholar] [CrossRef]
  186. Sun, W.-Y.; Tyurin, V.A.; Mikulska-Ruminska, K.; Shrivastava, I.H.; Anthonymuthu, T.S.; Zhai, Y.-J.; Pan, M.-H.; Gong, H.-B.; Lu, D.-H.; Sun, J.; et al. Phospholipase iPLA2β Averts Ferroptosis by Eliminating a Redox Lipid Death Signal. Nat. Chem. Biol. 2021, 17, 465–476. [Google Scholar] [CrossRef] [PubMed]
  187. Toppo, S.; Flohé, L.; Ursini, F.; Vanin, S.; Maiorino, M. Catalytic Mechanisms and Specificities of Glutathione Peroxidases: Variations of a Basic Scheme. Biochim. Biophys. Acta 2009, 1790, 1486–1500. [Google Scholar] [CrossRef]
  188. Brigelius-Flohé, R.; Flohé, L. Regulatory Phenomena in the Glutathione Peroxidase Superfamily. Antioxid. Redox Signal. 2020, 33, 498–516. [Google Scholar] [CrossRef]
  189. Xie, Y.; Kang, R.; Klionsky, D.J.; Tang, D. GPX4 in Cell Death, Autophagy, and Disease. Autophagy 2023, 19, 2621–2638. [Google Scholar] [CrossRef] [PubMed]
  190. Maiorino, M.; Conrad, M.; Ursini, F. GPx4, Lipid Peroxidation, and Cell Death: Discoveries, Rediscoveries, and Open Issues. Antioxid. Redox Signal. 2018, 29, 61–74. [Google Scholar] [CrossRef]
  191. Ingold, I.; Berndt, C.; Schmitt, S.; Doll, S.; Poschmann, G.; Buday, K.; Roveri, A.; Peng, X.; Porto Freitas, F.; Seibt, T.; et al. Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell 2018, 172, 409–422.e21. [Google Scholar] [CrossRef]
  192. Schnurr, K.; Belkner, J.; Ursini, F.; Schewe, T.; Kühn, H. The Selenoenzyme Phospholipid Hydroperoxide Glutathione Peroxidase Controls the Activity of the 15-Lipoxygenase with Complex Substrates and Preserves the Specificity of the Oxygenation Products. J. Biol. Chem. 1996, 271, 4653–4658. [Google Scholar] [CrossRef]
  193. Imai, H.; Hirao, F.; Sakamoto, T.; Sekine, K.; Mizukura, Y.; Saito, M.; Kitamoto, T.; Hayasaka, M.; Hanaoka, K.; Nakagawa, Y. Early Embryonic Lethality Caused by Targeted Disruption of the Mouse PHGPx Gene. Biochem. Biophys. Res. Commun. 2003, 305, 278–286. [Google Scholar] [CrossRef]
  194. Yant, L.J.; Ran, Q.; Rao, L.; Van Remmen, H.; Shibatani, T.; Belter, J.G.; Motta, L.; Richardson, A.; Prolla, T.A. The Selenoprotein GPX4 Is Essential for Mouse Development and Protects from Radiation and Oxidative Damage Insults. Free Radic. Biol. Med. 2003, 34, 496–502. [Google Scholar] [CrossRef]
  195. Garry, M.R.; Kavanagh, T.J.; Faustman, E.M.; Sidhu, J.S.; Liao, R.; Ware, C.; Vliet, P.A.; Deeb, S.S. Sensitivity of Mouse Lung Fibroblasts Heterozygous for GPx4 to Oxidative Stress. Free Radic. Biol. Med. 2008, 44, 1075–1087. [Google Scholar] [CrossRef] [PubMed]
  196. de Haan, J.B.; Bladier, C.; Lotfi-Miri, M.; Taylor, J.; Hutchinson, P.; Crack, P.J.; Hertzog, P.; Kola, I. Fibroblasts Derived from Gpx1 Knockout Mice Display Senescent-like Features and Are Susceptible to H2O2-Mediated Cell Death. Free Radic. Biol. Med. 2004, 36, 53–64. [Google Scholar] [CrossRef]
  197. Seiler, A.; Schneider, M.; Förster, H.; Roth, S.; Wirth, E.K.; Culmsee, C.; Plesnila, N.; Kremmer, E.; Rådmark, O.; Wurst, W.; et al. Glutathione Peroxidase 4 Senses and Translates Oxidative Stress into 12/15-Lipoxygenase Dependent- and AIF-Mediated Cell Death. Cell Metab. 2008, 8, 237–248. [Google Scholar] [CrossRef]
  198. Yang, W.S.; SriRamaratnam, R.; Welsch, M.E.; Shimada, K.; Skouta, R.; Viswanathan, V.S.; Cheah, J.H.; Clemons, P.A.; Shamji, A.F.; Clish, C.B.; et al. Regulation of Ferroptotic Cancer Cell Death by GPX4. Cell 2014, 156, 317–331. [Google Scholar] [CrossRef]
  199. Friedmann Angeli, J.P.; Schneider, M.; Proneth, B.; Tyurina, Y.Y.; Tyurin, V.A.; Hammond, V.J.; Herbach, N.; Aichler, M.; Walch, A.; Eggenhofer, E.; et al. Inactivation of the Ferroptosis Regulator Gpx4 Triggers Acute Renal Failure in Mice. Nat. Cell Biol. 2014, 16, 1180–1191. [Google Scholar] [CrossRef]
  200. Zuo, S.; Yu, J.; Pan, H.; Lu, L. Novel Insights on Targeting Ferroptosis in Cancer Therapy. Biomark. Res. 2020, 8, 50. [Google Scholar] [CrossRef] [PubMed]
  201. Nakamura, H.; Takada, K. Reactive Oxygen Species in Cancer: Current Findings and Future Directions. Cancer Sci. 2021, 112, 3945–3952. [Google Scholar] [CrossRef] [PubMed]
  202. Gorrini, C.; Harris, I.S.; Mak, T.W. Modulation of Oxidative Stress as an Anticancer Strategy. Nat. Rev. Drug Discov. 2013, 12, 931–947. [Google Scholar] [CrossRef]
  203. Combs, J.A.; DeNicola, G.M. The Non-Essential Amino Acid Cysteine Becomes Essential for Tumor Proliferation and Survival. Cancers 2019, 11, 678. [Google Scholar] [CrossRef]
  204. Bonifácio, V.D.B.; Pereira, S.A.; Serpa, J.; Vicente, J.B. Cysteine Metabolic Circuitries: Druggable Targets in Cancer. Br. J. Cancer 2021, 124, 862–879. [Google Scholar] [CrossRef] [PubMed]
  205. Harris, I.S.; DeNicola, G.M. The Complex Interplay between Antioxidants and ROS in Cancer. Trends Cell Biol. 2020, 30, 440–451. [Google Scholar] [CrossRef] [PubMed]
  206. Shi, H.; Bencze, K.Z.; Stemmler, T.L.; Philpott, C.C. A Cytosolic Iron Chaperone That Delivers Iron to Ferritin. Science 2008, 320, 1207–1210. [Google Scholar] [CrossRef]
  207. Patel, S.J.; Protchenko, O.; Shakoury-Elizeh, M.; Baratz, E.; Jadhav, S.; Philpott, C.C. The Iron Chaperone and Nucleic Acid-Binding Activities of Poly(rC)-Binding Protein 1 Are Separable and Independently Essential. Proc. Natl. Acad. Sci. USA 2021, 118, e2104666118. [Google Scholar] [CrossRef] [PubMed]
  208. Soula, M.; Weber, R.A.; Zilka, O.; Alwaseem, H.; La, K.; Yen, F.; Molina, H.; Garcia-Bermudez, J.; Pratt, D.A.; Birsoy, K. Metabolic Determinants of Cancer Cell Sensitivity to Canonical Ferroptosis Inducers. Nat. Chem. Biol. 2020, 16, 1351–1360. [Google Scholar] [CrossRef] [PubMed]
  209. Murphy, T.H.; Miyamoto, M.; Sastre, A.; Schnaar, R.L.; Coyle, J.T. Glutamate Toxicity in a Neuronal Cell Line Involves Inhibition of Cystine Transport Leading to Oxidative Stress. Neuron 1989, 2, 1547–1558. [Google Scholar] [CrossRef] [PubMed]
  210. Sato, H.; Tamba, M.; Ishii, T.; Bannai, S. Cloning and Expression of a Plasma Membrane Cystine/Glutamate Exchange Transporter Composed of Two Distinct Proteins. J. Biol. Chem. 1999, 274, 11455–11458. [Google Scholar] [CrossRef]
  211. Pader, I.; Sengupta, R.; Cebula, M.; Xu, J.; Lundberg, J.O.; Holmgren, A.; Johansson, K.; Arnér, E.S.J. Thioredoxin-Related Protein of 14 kDa Is an Efficient L-Cystine Reductase and S-Denitrosylase. Proc. Natl. Acad. Sci. USA 2014, 111, 6964–6969. [Google Scholar] [CrossRef]
  212. Poltorack, C.D.; Dixon, S.J. Understanding the Role of Cysteine in Ferroptosis: Progress & Paradoxes. FEBS J. 2022, 289, 374–385. [Google Scholar] [CrossRef]
  213. Cramer, S.L.; Saha, A.; Liu, J.; Tadi, S.; Tiziani, S.; Yan, W.; Triplett, K.; Lamb, C.; Alters, S.E.; Rowlinson, S.; et al. Systemic Depletion of L-Cyst(e)Ine with Cyst(e)Inase Increases Reactive Oxygen Species and Suppresses Tumor Growth. Nat. Med. 2017, 23, 120–127. [Google Scholar] [CrossRef]
  214. Koppula, P.; Zhang, Y.; Zhuang, L.; Gan, B. Amino Acid Transporter SLC7A11/xCT at the Crossroads of Regulating Redox Homeostasis and Nutrient Dependency of Cancer. Cancer Commun. 2018, 38, 12. [Google Scholar] [CrossRef]
  215. Liu, M.-R.; Zhu, W.-T.; Pei, D.-S. System Xc-: A Key Regulatory Target of Ferroptosis in Cancer. Investig. New Drugs 2021, 39, 1123–1131. [Google Scholar] [CrossRef]
  216. Yan, Y.; Teng, H.; Hang, Q.; Kondiparthi, L.; Lei, G.; Horbath, A.; Liu, X.; Mao, C.; Wu, S.; Zhuang, L.; et al. SLC7A11 Expression Level Dictates Differential Responses to Oxidative Stress in Cancer Cells. Nat. Commun. 2023, 14, 3673. [Google Scholar] [CrossRef]
  217. Griffith, O.W.; Bridges, R.J.; Meister, A. Evidence That the Gamma-Glutamyl Cycle Functions in Vivo Using Intracellular Glutathione: Effects of Amino Acids and Selective Inhibition of Enzymes. Proc. Natl. Acad. Sci. USA 1978, 75, 5405–5408. [Google Scholar] [CrossRef]
  218. Hayashima, K.; Katoh, H. Expression of Gamma-Glutamyltransferase 1 in Glioblastoma Cells Confers Resistance to Cystine Deprivation-Induced Ferroptosis. J. Biol. Chem. 2022, 298, 101703. [Google Scholar] [CrossRef]
  219. Xu, G.; Wang, J.; Zhang, Y.; Chen, Z.; Deng, R. GGT1 Suppresses the Development of Ferroptosis and Autophagy in Mouse Retinal Ganglion Cell Through Targeting GCLC. Eye Brain 2023, 15, 139–151. [Google Scholar] [CrossRef] [PubMed]
  220. Pajares, M.A.; Pérez-Sala, D. Mammalian Sulfur Amino Acid Metabolism: A Nexus Between Redox Regulation, Nutrition, Epigenetics, and Detoxification. Antioxid. Redox Signal. 2018, 29, 408–452. [Google Scholar] [CrossRef] [PubMed]
  221. Liu, S.; Wu, W.; Chen, Q.; Zheng, Z.; Jiang, X.; Xue, Y.; Lin, D. TXNRD1: A Key Regulator Involved in the Ferroptosis of CML Cells Induced by Cysteine Depletion In Vitro. Oxidative Med. Cell. Longev. 2021, 2021, 7674565. [Google Scholar] [CrossRef] [PubMed]
  222. Du, C.; Xu, H.; Cao, C.; Cao, J.; Zhang, Y.; Zhang, C.; Qiao, R.; Ming, W.; Li, Y.; Ren, H.; et al. Neutral Amino Acid Transporter SLC38A2 Protects Renal Medulla from Hyperosmolarity-Induced Ferroptosis. eLife 2023, 12, e80647. [Google Scholar] [CrossRef] [PubMed]
  223. Zhang, H.-F.; Klein Geltink, R.I.; Parker, S.J.; Sorensen, P.H. Transsulfuration, Minor Player or Crucial for Cysteine Homeostasis in Cancer. Trends Cell Biol. 2022, 32, 800–814. [Google Scholar] [CrossRef] [PubMed]
  224. Sbodio, J.I.; Snyder, S.H.; Paul, B.D. Regulators of the Transsulfuration Pathway. Br. J. Pharmacol. 2019, 176, 583–593. [Google Scholar] [CrossRef]
  225. Hayano, M.; Yang, W.S.; Corn, C.K.; Pagano, N.C.; Stockwell, B.R. Loss of Cysteinyl-tRNA Synthetase (CARS) Induces the Transsulfuration Pathway and Inhibits Ferroptosis Induced by Cystine Deprivation. Cell Death Differ. 2016, 23, 270–278. [Google Scholar] [CrossRef]
  226. Wang, L.; Cai, H.; Hu, Y.; Liu, F.; Huang, S.; Zhou, Y.; Yu, J.; Xu, J.; Wu, F. A Pharmacological Probe Identifies Cystathionine β-Synthase as a New Negative Regulator for Ferroptosis. Cell Death Dis. 2018, 9, 1005. [Google Scholar] [CrossRef]
  227. Cao, J.; Chen, X.; Jiang, L.; Lu, B.; Yuan, M.; Zhu, D.; Zhu, H.; He, Q.; Yang, B.; Ying, M. DJ-1 Suppresses Ferroptosis through Preserving the Activity of S-Adenosyl Homocysteine Hydrolase. Nat. Commun. 2020, 11, 1251. [Google Scholar] [CrossRef]
  228. Liao, T.; Xu, X.; Ye, X.; Yan, J. DJ-1 Upregulates the Nrf2/GPX4 Signal Pathway to Inhibit Trophoblast Ferroptosis in the Pathogenesis of Preeclampsia. Sci. Rep. 2022, 12, 2934. [Google Scholar] [CrossRef] [PubMed]
  229. Kobayashi, S.; Sato, M.; Kasakoshi, T.; Tsutsui, T.; Sugimoto, M.; Osaki, M.; Okada, F.; Igarashi, K.; Hiratake, J.; Homma, T.; et al. Cystathionine Is a Novel Substrate of Cystine/Glutamate Transporter: Implications for Immune Function. J. Biol. Chem. 2015, 290, 8778–8788. [Google Scholar] [CrossRef]
  230. Peng, H.; Zhu, M.; Kong, W.; Tang, C.; Du, J.; Huang, Y.; Jin, H. L-Cystathionine Protects against Oxidative Stress and DNA Damage Induced by Oxidized Low-Density Lipoprotein in THP-1-Derived Macrophages. Front. Pharmacol. 2023, 14, 1161542. [Google Scholar] [CrossRef]
  231. Fisher, A.B.; Vasquez-Medina, J.P.; Dodia, C.; Sorokina, E.M.; Tao, J.-Q.; Feinstein, S.I. Peroxiredoxin 6 Phospholipid Hydroperoxidase Activity in the Repair of Peroxidized Cell Membranes. Redox Biol. 2018, 14, 41–46. [Google Scholar] [CrossRef]
  232. Perkins, A.; Nelson, K.J.; Parsonage, D.; Poole, L.B.; Karplus, P.A. Peroxiredoxins: Guardians against Oxidative Stress and Modulators of Peroxide Signaling. Trends Biochem. Sci. 2015, 40, 435–445. [Google Scholar] [CrossRef] [PubMed]
  233. Fisher, A.B.; Dodia, C.; Sorokina, E.M.; Li, H.; Zhou, S.; Raabe, T.; Feinstein, S.I. A Novel Lysophosphatidylcholine Acyl Transferase Activity Is Expressed by Peroxiredoxin 6. J. Lipid Res. 2016, 57, 587–596. [Google Scholar] [CrossRef]
  234. Fisher, A.B. Peroxiredoxin 6 in the Repair of Peroxidized Cell Membranes and Cell Signaling. Arch. Biochem. Biophys. 2017, 617, 68–83. [Google Scholar] [CrossRef] [PubMed]
  235. Arevalo, J.A.; Vázquez-Medina, J.P. The Role of Peroxiredoxin 6 in Cell Signaling. Antioxidants 2018, 7, 172. [Google Scholar] [CrossRef] [PubMed]
  236. Lu, B.; Chen, X.-B.; Hong, Y.-C.; Zhu, H.; He, Q.-J.; Yang, B.; Ying, M.-D.; Cao, J. Identification of PRDX6 as a Regulator of Ferroptosis. Acta Pharmacol. Sin. 2019, 40, 1334–1342. [Google Scholar] [CrossRef]
  237. Liao, J.; Xie, S.-S.; Deng, Y.; Wu, D.-D.; Meng, H.; Lan, W.-F.; Dai, P. PRDX6-Mediated Pulmonary Artery Endothelial Cell Ferroptosis Contributes to Monocrotaline-Induced Pulmonary Hypertension. Microvasc. Res. 2023, 146, 104471. [Google Scholar] [CrossRef] [PubMed]
  238. Yang, H.; Wang, H.; Andersson, U. Targeting Inflammation Driven by HMGB1. Front. Immunol. 2020, 11, 484. [Google Scholar] [CrossRef]
  239. Zhang, Q.; Hu, Y.; Hu, J.-E.; Ding, Y.; Shen, Y.; Xu, H.; Chen, H.; Wu, N. Sp1-Mediated Upregulation of Prdx6 Expression Prevents Podocyte Injury in Diabetic Nephropathy via Mitigation of Oxidative Stress and Ferroptosis. Life Sci. 2021, 278, 119529. [Google Scholar] [CrossRef]
  240. Liu, J.; Sun, L.; Chen, D.; Huo, X.; Tian, X.; Li, J.; Liu, M.; Yu, Z.; Zhang, B.; Yang, Y.; et al. Prdx6-Induced Inhibition of Ferroptosis in Epithelial Cells Contributes to Liquiritin-Exerted Alleviation of Colitis. Food Funct. 2022, 13, 9470–9480. [Google Scholar] [CrossRef]
  241. Yang, L.; Fan, X.; Zhou, C.; Wang, Z.; Cui, Z.; Wu, X.; Xu, Z.; Yang, J.; Zhang, X. Construction and Validation of a Novel Ferroptosis-Related Prognostic Signature for Lung Adenocarcinoma. Transl. Lung Cancer Res. 2023, 12, 1766–1781. [Google Scholar] [CrossRef]
  242. Li, Z.; Xiao, J.; Liu, M.; Cui, J.; Lian, B.; Sun, Y.; Li, C. Notch3 Regulates Ferroptosis via ROS-Induced Lipid Peroxidation in NSCLC Cells. FEBS Open Bio 2022, 12, 1197–1205. [Google Scholar] [CrossRef]
  243. Holstein, S.A.; Hohl, R.J. Isoprenoids: Remarkable Diversity of Form and Function. Lipids 2004, 39, 293–309. [Google Scholar] [CrossRef]
  244. Viswanathan, V.S.; Ryan, M.J.; Dhruv, H.D.; Gill, S.; Eichhoff, O.M.; Seashore-Ludlow, B.; Kaffenberger, S.D.; Eaton, J.K.; Shimada, K.; Aguirre, A.J.; et al. Dependency of a Therapy-Resistant State of Cancer Cells on a Lipid Peroxidase Pathway. Nature 2017, 547, 453–457. [Google Scholar] [CrossRef] [PubMed]
  245. Friedmann Angeli, J.P.; Conrad, M. Selenium and GPX4, a Vital Symbiosis. Free Radic. Biol. Med. 2018, 127, 153–159. [Google Scholar] [CrossRef] [PubMed]
  246. Warner, G.J.; Berry, M.J.; Moustafa, M.E.; Carlson, B.A.; Hatfield, D.L.; Faust, J.R. Inhibition of Selenoprotein Synthesis by Selenocysteine tRNA[Ser]Sec Lacking Isopentenyladenosine. J. Biol. Chem. 2000, 275, 28110–28119. [Google Scholar] [CrossRef] [PubMed]
  247. Shimada, K.; Skouta, R.; Kaplan, A.; Yang, W.S.; Hayano, M.; Dixon, S.J.; Brown, L.M.; Valenzuela, C.A.; Wolpaw, A.J.; Stockwell, B.R. Global Survey of Cell Death Mechanisms Reveals Metabolic Regulation of Ferroptosis. Nat. Chem. Biol. 2016, 12, 497–503. [Google Scholar] [CrossRef] [PubMed]
  248. Pallotti, F.; Bergamini, C.; Lamperti, C.; Fato, R. The Roles of Coenzyme Q in Disease: Direct and Indirect Involvement in Cellular Functions. Int. J. Mol. Sci. 2021, 23, 128. [Google Scholar] [CrossRef] [PubMed]
  249. Doll, S.; Freitas, F.P.; Shah, R.; Aldrovandi, M.; da Silva, M.C.; Ingold, I.; Goya Grocin, A.; Xavier da Silva, T.N.; Panzilius, E.; Scheel, C.H.; et al. FSP1 Is a Glutathione-Independent Ferroptosis Suppressor. Nature 2019, 575, 693–698. [Google Scholar] [CrossRef] [PubMed]
  250. Bersuker, K.; Hendricks, J.M.; Li, Z.; Magtanong, L.; Ford, B.; Tang, P.H.; Roberts, M.A.; Tong, B.; Maimone, T.J.; Zoncu, R.; et al. The CoQ Oxidoreductase FSP1 Acts Parallel to GPX4 to Inhibit Ferroptosis. Nature 2019, 575, 688–692. [Google Scholar] [CrossRef]
  251. Zeng, F.; Chen, X.; Deng, G. The Anti-Ferroptotic Role of FSP1: Current Molecular Mechanism and Therapeutic Approach. Mol. Biomed. 2022, 3, 37. [Google Scholar] [CrossRef]
  252. Li, W.; Liang, L.; Liu, S.; Yi, H.; Zhou, Y. FSP1: A Key Regulator of Ferroptosis. Trends Mol. Med. 2023, 29, 753–764. [Google Scholar] [CrossRef]
  253. Mishima, E.; Ito, J.; Wu, Z.; Nakamura, T.; Wahida, A.; Doll, S.; Tonnus, W.; Nepachalovich, P.; Eggenhofer, E.; Aldrovandi, M.; et al. A Non-Canonical Vitamin K Cycle Is a Potent Ferroptosis Suppressor. Nature 2022, 608, 778–783. [Google Scholar] [CrossRef]
  254. Lv, Y.; Liang, C.; Sun, Q.; Zhu, J.; Xu, H.; Li, X.; Li, Y.-Y.; Wang, Q.; Yuan, H.; Chu, B.; et al. Structural Insights into FSP1 Catalysis and Ferroptosis Inhibition. Nat. Commun. 2023, 14, 5933. [Google Scholar] [CrossRef] [PubMed]
  255. Dai, E.; Zhang, W.; Cong, D.; Kang, R.; Wang, J.; Tang, D. AIFM2 Blocks Ferroptosis Independent of Ubiquinol Metabolism. Biochem. Biophys. Res. Commun. 2020, 523, 966–971. [Google Scholar] [CrossRef] [PubMed]
  256. Dai, E.; Meng, L.; Kang, R.; Wang, X.; Tang, D. ESCRT-III-Dependent Membrane Repair Blocks Ferroptosis. Biochem. Biophys. Res. Commun. 2020, 522, 415–421. [Google Scholar] [CrossRef]
  257. Liu, J.; Kang, R.; Tang, D. ESCRT-III-Mediated Membrane Repair in Cell Death and Tumor Resistance. Cancer Gene Ther. 2021, 28, 1–4. [Google Scholar] [CrossRef]
  258. Yoshioka, H.; Kawamura, T.; Muroi, M.; Kondoh, Y.; Honda, K.; Kawatani, M.; Aono, H.; Waldmann, H.; Watanabe, N.; Osada, H. Identification of a Small Molecule That Enhances Ferroptosis via Inhibition of Ferroptosis Suppressor Protein 1 (FSP1). ACS Chem. Biol. 2022, 17, 483–491. [Google Scholar] [CrossRef]
  259. Zhang, S.; Gou, S.; Zhang, Q.; Yong, X.; Gan, B.; Jia, D. FSP1 Oxidizes NADPH to Suppress Ferroptosis. Cell Res. 2023, 33, 967–970. [Google Scholar] [CrossRef]
  260. Koppula, P.; Lei, G.; Zhang, Y.; Yan, Y.; Mao, C.; Kondiparthi, L.; Shi, J.; Liu, X.; Horbath, A.; Das, M.; et al. A Targetable CoQ-FSP1 Axis Drives Ferroptosis- and Radiation-Resistance in KEAP1 Inactive Lung Cancers. Nat. Commun. 2022, 13, 2206. [Google Scholar] [CrossRef]
  261. Lee, J.; Roh, J.-L. Unleashing Ferroptosis in Human Cancers: Targeting Ferroptosis Suppressor Protein 1 for Overcoming Therapy Resistance. Antioxidants 2023, 12, 1218. [Google Scholar] [CrossRef] [PubMed]
  262. Vasan, K.; Werner, M.; Chandel, N.S. Mitochondrial Metabolism as a Target for Cancer Therapy. Cell Metab. 2020, 32, 341–352. [Google Scholar] [CrossRef]
  263. Mráček, T.; Drahota, Z.; Houštěk, J. The Function and the Role of the Mitochondrial Glycerol-3-Phosphate Dehydrogenase in Mammalian Tissues. Biochim. Biophys. Acta 2013, 1827, 401–410. [Google Scholar] [CrossRef]
  264. Kraft, V.A.N.; Bezjian, C.T.; Pfeiffer, S.; Ringelstetter, L.; Müller, C.; Zandkarimi, F.; Merl-Pham, J.; Bao, X.; Anastasov, N.; Kössl, J.; et al. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Cent. Sci. 2020, 6, 41–53. [Google Scholar] [CrossRef]
  265. Hu, Q.; Wei, W.; Wu, D.; Huang, F.; Li, M.; Li, W.; Yin, J.; Peng, Y.; Lu, Y.; Zhao, Q.; et al. Blockade of GCH1/BH4 Axis Activates Ferritinophagy to Mitigate the Resistance of Colorectal Cancer to Erastin-Induced Ferroptosis. Front. Cell Dev. Biol. 2022, 10, 810327. [Google Scholar] [CrossRef] [PubMed]
  266. Wang, D.; Liang, W.; Huo, D.; Wang, H.; Wang, Y.; Cong, C.; Zhang, C.; Yan, S.; Gao, M.; Su, X.; et al. SPY1 Inhibits Neuronal Ferroptosis in Amyotrophic Lateral Sclerosis by Reducing Lipid Peroxidation through Regulation of GCH1 and TFR1. Cell Death Differ. 2023, 30, 369–382. [Google Scholar] [CrossRef]
  267. Kuang, F.; Liu, J.; Xie, Y.; Tang, D.; Kang, R. MGST1 Is a Redox-Sensitive Repressor of Ferroptosis in Pancreatic Cancer Cells. Cell Chem. Biol. 2021, 28, 765–775.e5. [Google Scholar] [CrossRef] [PubMed]
  268. Johansson, K.; Järvliden, J.; Gogvadze, V.; Morgenstern, R. Multiple Roles of Microsomal Glutathione Transferase 1 in Cellular Protection: A Mechanistic Study. Free Radic. Biol. Med. 2010, 49, 1638–1645. [Google Scholar] [CrossRef] [PubMed]
  269. Morgenstern, R.; Zhang, J.; Johansson, K. Microsomal Glutathione Transferase 1: Mechanism and Functional Roles. Drug Metab. Rev. 2011, 43, 300–306. [Google Scholar] [CrossRef] [PubMed]
  270. Peng, Z.; Peng, N. Microsomal Glutathione S-Transferase 1 Targets the Autophagy Signaling Pathway to Suppress Ferroptosis in Gastric Carcinoma Cells. Hum. Exp. Toxicol. 2023, 42, 9603271231172915. [Google Scholar] [CrossRef] [PubMed]
  271. Chen, F.; Cai, X.; Kang, R.; Liu, J.; Tang, D. Autophagy-Dependent Ferroptosis in Cancer. Antioxid. Redox Signal. 2023, 39, 79–101. [Google Scholar] [CrossRef] [PubMed]
  272. Yang, M.; Chen, P.; Liu, J.; Zhu, S.; Kroemer, G.; Klionsky, D.J.; Lotze, M.T.; Zeh, H.J.; Kang, R.; Tang, D. Clockophagy Is a Novel Selective Autophagy Process Favoring Ferroptosis. Sci. Adv. 2019, 5, eaaw2238. [Google Scholar] [CrossRef]
  273. Rižner, T.L.; Penning, T.M. Role of Aldo-Keto Reductase Family 1 (AKR1) Enzymes in Human Steroid Metabolism. Steroids 2014, 79, 49–63. [Google Scholar] [CrossRef]
  274. Burczynski, M.E.; Sridhar, G.R.; Palackal, N.T.; Penning, T.M. The Reactive Oxygen Species--and Michael Acceptor-Inducible Human Aldo-Keto Reductase AKR1C1 Reduces the Alpha,Beta-Unsaturated Aldehyde 4-Hydroxy-2-Nonenal to 1,4-Dihydroxy-2-Nonene. J. Biol. Chem. 2001, 276, 2890–2897. [Google Scholar] [CrossRef]
  275. Gagliardi, M.; Cotella, D.; Santoro, C.; Corà, D.; Barlev, N.A.; Piacentini, M.; Corazzari, M. Aldo-Keto Reductases Protect Metastatic Melanoma from ER Stress-Independent Ferroptosis. Cell Death Dis. 2019, 10, 902. [Google Scholar] [CrossRef]
  276. Zuo, X.; Zeng, H.; Wang, B.; Yang, X.; He, D.; Wang, L.; Ouyang, H.; Yuan, J. AKR1C1 Protects Corneal Epithelial Cells Against Oxidative Stress-Mediated Ferroptosis in Dry Eye. Investig. Ophthalmol. Vis. Sci. 2022, 63, 3. [Google Scholar] [CrossRef]
  277. Tesfay, L.; Paul, B.T.; Konstorum, A.; Deng, Z.; Cox, A.O.; Lee, J.; Furdui, C.M.; Hegde, P.; Torti, F.M.; Torti, S.V. Stearoyl-CoA Desaturase 1 Protects Ovarian Cancer Cells from Ferroptotic Cell Death. Cancer Res. 2019, 79, 5355–5366. [Google Scholar] [CrossRef] [PubMed]
  278. Luo, H.; Wang, X.; Song, S.; Wang, Y.; Dan, Q.; Ge, H. Targeting Stearoyl-Coa Desaturase Enhances Radiation Induced Ferroptosis and Immunogenic Cell Death in Esophageal Squamous Cell Carcinoma. OncoImmunology 2022, 11, 2101769. [Google Scholar] [CrossRef] [PubMed]
  279. Yi, J.; Zhu, J.; Wu, J.; Thompson, C.B.; Jiang, X. Oncogenic Activation of PI3K-AKT-mTOR Signaling Suppresses Ferroptosis via SREBP-Mediated Lipogenesis. Proc. Natl. Acad. Sci. USA 2020, 117, 31189–31197. [Google Scholar] [CrossRef] [PubMed]
  280. Tang, Y.; Zhou, J.; Hooi, S.C.; Jiang, Y.-M.; Lu, G.-D. Fatty Acid Activation in Carcinogenesis and Cancer Development: Essential Roles of Long-Chain Acyl-CoA Synthetases. Oncol. Lett. 2018, 16, 1390–1396. [Google Scholar] [CrossRef] [PubMed]
  281. Li, C.; Gui, G.; Zhang, L.; Qin, A.; Zhou, C.; Zha, X. Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors. J. Med. Chem. 2022, 65, 9531–9547. [Google Scholar] [CrossRef] [PubMed]
  282. Ma, M.; Kong, P.; Huang, Y.; Wang, J.; Liu, X.; Hu, Y.; Chen, X.; Du, C.; Yang, H. Activation of MAT2A-ACSL3 Pathway Protects Cells from Ferroptosis in Gastric Cancer. Free Radic. Biol. Med. 2022, 181, 288–299. [Google Scholar] [CrossRef]
  283. Shakya, A.; McKee, N.W.; Dodson, M.; Chapman, E.; Zhang, D.D. Anti-Ferroptotic Effects of Nrf2: Beyond the Antioxidant Response. Mol. Cells 2023, 46, 165–175. [Google Scholar] [CrossRef]
  284. Komatsu, M.; Kurokawa, H.; Waguri, S.; Taguchi, K.; Kobayashi, A.; Ichimura, Y.; Sou, Y.-S.; Ueno, I.; Sakamoto, A.; Tong, K.I.; et al. The Selective Autophagy Substrate P62 Activates the Stress Responsive Transcription Factor Nrf2 through Inactivation of Keap1. Nat. Cell Biol. 2010, 12, 213–223. [Google Scholar] [CrossRef]
  285. Cao, J.Y.; Poddar, A.; Magtanong, L.; Lumb, J.H.; Mileur, T.R.; Reid, M.A.; Dovey, C.M.; Wang, J.; Locasale, J.W.; Stone, E.; et al. A Genome-Wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity. Cell Rep. 2019, 26, 1544–1556.e8. [Google Scholar] [CrossRef] [PubMed]
  286. Jenkins, T.; Gouge, J. Nrf2 in Cancer, Detoxifying Enzymes and Cell Death Programs. Antioxidants 2021, 10, 1030. [Google Scholar] [CrossRef] [PubMed]
  287. Wang, X.-J.; Sun, Z.; Villeneuve, N.F.; Zhang, S.; Zhao, F.; Li, Y.; Chen, W.; Yi, X.; Zheng, W.; Wondrak, G.T.; et al. Nrf2 Enhances Resistance of Cancer Cells to Chemotherapeutic Drugs, the Dark Side of Nrf2. Carcinogenesis 2008, 29, 1235–1243. [Google Scholar] [CrossRef] [PubMed]
  288. Pouremamali, F.; Pouremamali, A.; Dadashpour, M.; Soozangar, N.; Jeddi, F. An Update of Nrf2 Activators and Inhibitors in Cancer Prevention/Promotion. Cell Commun. Signal. 2022, 20, 100. [Google Scholar] [CrossRef] [PubMed]
  289. Sun, X.; Ou, Z.; Chen, R.; Niu, X.; Chen, D.; Kang, R.; Tang, D. Activation of the p62-Keap1-NRF2 Pathway Protects against Ferroptosis in Hepatocellular Carcinoma Cells. Hepatology 2016, 63, 173–184. [Google Scholar] [CrossRef] [PubMed]
  290. Kim, J.W.; Kim, M.-J.; Han, T.-H.; Lee, J.-Y.; Kim, S.; Kim, H.; Oh, K.-J.; Kim, W.K.; Han, B.-S.; Bae, K.-H.; et al. FSP1 Confers Ferroptosis Resistance in KEAP1 Mutant Non-Small Cell Lung Carcinoma in NRF2-Dependent and -Independent Manner. Cell Death Dis. 2023, 14, 567. [Google Scholar] [CrossRef] [PubMed]
  291. Kerins, M.J.; Ooi, A. The Roles of NRF2 in Modulating Cellular Iron Homeostasis. Antioxid. Redox Signal. 2018, 29, 1756–1773. [Google Scholar] [CrossRef]
  292. Anandhan, A.; Dodson, M.; Shakya, A.; Chen, J.; Liu, P.; Wei, Y.; Tan, H.; Wang, Q.; Jiang, Z.; Yang, K.; et al. NRF2 Controls Iron Homeostasis and Ferroptosis through HERC2 and VAMP8. Sci. Adv. 2023, 9, eade9585. [Google Scholar] [CrossRef] [PubMed]
  293. Salazar, M.; Rojo, A.I.; Velasco, D.; De Sagarra, R.M.; Cuadrado, A. Glycogen Synthase Kinase-3β Inhibits the Xenobiotic and Antioxidant Cell Response by Direct Phosphorylation and Nuclear Exclusion of the Transcription Factor Nrf2. J. Biol. Chem. 2006, 281, 14841–14851. [Google Scholar] [CrossRef]
  294. Takahashi, N.; Cho, P.; Selfors, L.M.; Kuiken, H.J.; Kaul, R.; Fujiwara, T.; Harris, I.S.; Zhang, T.; Gygi, S.P.; Brugge, J.S. 3D Culture Models with CRISPR Screens Reveal Hyperactive NRF2 as a Prerequisite for Spheroid Formation via Regulation of Proliferation and Ferroptosis. Mol. Cell 2020, 80, 828–844.e6. [Google Scholar] [CrossRef] [PubMed]
  295. Venugopal, R.; Jaiswal, A.K. Nrf2 and Nrf1 in Association with Jun Proteins Regulate Antioxidant Response Element-Mediated Expression and Coordinated Induction of Genes Encoding Detoxifying Enzymes. Oncogene 1998, 17, 3145–3156. [Google Scholar] [CrossRef]
  296. He, C.H.; Gong, P.; Hu, B.; Stewart, D.; Choi, M.E.; Choi, A.M.K.; Alam, J. Identification of Activating Transcription Factor 4 (ATF4) as an Nrf2-Interacting Protein. J. Biol. Chem. 2001, 276, 20858–20865. [Google Scholar] [CrossRef]
  297. Zhang, X.-Y.; Zhang, H.; Hu, S.-J.; Liao, S.-Y.; Tao, D.-C.; Tan, X.-L.; Yi, M.; Leng, X.-Y.; Wang, Z.-K.; Shi, J.-Y.; et al. NR0B1 Suppresses Ferroptosis through Upregulation of NRF2/c-JUN-CBS Signaling Pathway in Lung Cancer Cells. Am. J. Cancer Res. 2023, 13, 5174–5196. [Google Scholar]
  298. Anandhan, A.; Dodson, M.; Schmidlin, C.J.; Liu, P.; Zhang, D.D. Breakdown of an Ironclad Defense System: The Critical Role of NRF2 in Mediating Ferroptosis. Cell Chem. Biol. 2020, 27, 436–447. [Google Scholar] [CrossRef]
  299. Chen, D.; Fan, Z.; Rauh, M.; Buchfelder, M.; Eyupoglu, I.Y.; Savaskan, N. ATF4 Promotes Angiogenesis and Neuronal Cell Death and Confers Ferroptosis in a xCT-Dependent Manner. Oncogene 2017, 36, 5593–5608. [Google Scholar] [CrossRef] [PubMed]
  300. Bhoumik, A.; Lopez-Bergami, P.; Ronai, Z. ATF2 on the Double-Activating Transcription Factor and DNA Damage Response Protein. Pigment Cell Res. 2007, 20, 498–506. [Google Scholar] [CrossRef] [PubMed]
  301. Xu, X.; Li, Y.; Wu, Y.; Wang, M.; Lu, Y.; Fang, Z.; Wang, H.; Li, Y. Increased ATF2 Expression Predicts Poor Prognosis and Inhibits Sorafenib-Induced Ferroptosis in Gastric Cancer. Redox Biol. 2023, 59, 102564. [Google Scholar] [CrossRef]
  302. Wang, L.; Chen, Y.; Mi, Y.; Qiao, J.; Jin, H.; Li, J.; Lu, Z.; Wang, Q.; Zou, Z. ATF2 Inhibits Ani-Tumor Effects of BET Inhibitor in a Negative Feedback Manner by Attenuating Ferroptosis. Biochem. Biophys. Res. Commun. 2021, 558, 216–223. [Google Scholar] [CrossRef]
  303. Ju, H.; Yun, H.; Kim, Y.; Nam, Y.J.; Lee, S.; Lee, J.; Jeong, S.M.; Heo, J.; Kwon, H.; Cho, Y.S.; et al. Activating Transcription Factor-2 Supports the Antioxidant Capacity and Ability of Human Mesenchymal Stem Cells to Prevent Asthmatic Airway Inflammation. Exp. Mol. Med. 2023, 55, 413–425. [Google Scholar] [CrossRef] [PubMed]
  304. Wu, J.; Huang, Y.; Zhou, X.; Xiang, Z.; Yang, Z.; Meng, D.; Wu, D.; Zhang, J.; Yang, J. ATF3 and Its Emerging Role in Atherosclerosis: A Narrative Review. Cardiovasc. Diagn. Ther. 2022, 12, 926–942. [Google Scholar] [CrossRef] [PubMed]
  305. Ku, H.-C.; Cheng, C.-F. Master Regulator Activating Transcription Factor 3 (ATF3) in Metabolic Homeostasis and Cancer. Front. Endocrinol. 2020, 11, 556. [Google Scholar] [CrossRef] [PubMed]
  306. Wang, L.; Liu, Y.; Du, T.; Yang, H.; Lei, L.; Guo, M.; Ding, H.-F.; Zhang, J.; Wang, H.; Chen, X.; et al. ATF3 Promotes Erastin-Induced Ferroptosis by Suppressing System Xc−. Cell Death Differ. 2020, 27, 662–675. [Google Scholar] [CrossRef] [PubMed]
  307. Li, Y.; Yan, J.; Zhao, Q.; Zhang, Y.; Zhang, Y. ATF3 Promotes Ferroptosis in Sorafenib-Induced Cardiotoxicity by Suppressing Slc7a11 Expression. Front. Pharmacol. 2022, 13, 904314. [Google Scholar] [CrossRef] [PubMed]
  308. Chen, X.; Wang, Z.; Li, C.; Zhang, Z.; Lu, S.; Wang, X.; Liang, Q.; Zhu, X.; Pan, C.; Wang, Q.; et al. SIRT1 Activated by AROS Sensitizes Glioma Cells to Ferroptosis via Induction of NAD+ Depletion-Dependent Activation of ATF3. Redox Biol. 2024, 69, 103030. [Google Scholar] [CrossRef]
  309. Ameri, K.; Harris, A.L. Activating Transcription Factor 4. Int. J. Biochem. Cell Biol. 2008, 40, 14–21. [Google Scholar] [CrossRef]
  310. Zhu, S.; Zhang, Q.; Sun, X.; Zeh, H.J.; Lotze, M.T.; Kang, R.; Tang, D. HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells. Cancer Res. 2017, 77, 2064–2077. [Google Scholar] [CrossRef]
  311. Meinert, M.; Jessen, C.; Hufnagel, A.; Kreß, J.K.C.; Burnworth, M.; Däubler, T.; Gallasch, T.; Xavier Da Silva, T.N.; Dos Santos, A.F.; Ade, C.P.; et al. Thiol Starvation Triggers Melanoma State Switching in an ATF4 and NRF2-Dependent Manner. Redox Biol. 2024, 70, 103011. [Google Scholar] [CrossRef]
  312. Gao, R.; Kalathur, R.K.R.; Coto-Llerena, M.; Ercan, C.; Buechel, D.; Shuang, S.; Piscuoglio, S.; Dill, M.T.; Camargo, F.D.; Christofori, G.; et al. YAP/TAZ and ATF4 Drive Resistance to Sorafenib in Hepatocellular Carcinoma by Preventing Ferroptosis. EMBO Mol. Med. 2021, 13, e14351. [Google Scholar] [CrossRef] [PubMed]
  313. He, F.; Zhang, P.; Liu, J.; Wang, R.; Kaufman, R.J.; Yaden, B.C.; Karin, M. ATF4 Suppresses Hepatocarcinogenesis by Inducing SLC7A11 (xCT) to Block Stress-Related Ferroptosis. J. Hepatol. 2023, 79, 362–377. [Google Scholar] [CrossRef] [PubMed]
  314. Jin, C.; Luo, Y.; Liang, Z.; Li, X.; Kołat, D.; Zhao, L.; Xiong, W. Crucial Role of the Transcription Factors Family Activator Protein 2 in Cancer: Current Clue and Views. J. Transl. Med. 2023, 21, 371. [Google Scholar] [CrossRef] [PubMed]
  315. Huang, H.-X.; Yang, G.; Yang, Y.; Yan, J.; Tang, X.-Y.; Pan, Q. TFAP2A Is a Novel Regulator That Modulates Ferroptosis in Gallbladder Carcinoma Cells via the Nrf2 Signalling Axis. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 4745–4755. [Google Scholar] [CrossRef] [PubMed]
  316. Alim, I.; Caulfield, J.T.; Chen, Y.; Swarup, V.; Geschwind, D.H.; Ivanova, E.; Seravalli, J.; Ai, Y.; Sansing, L.H.; Ste.Marie, E.J.; et al. Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. Cell 2019, 177, 1262–1279.e25. [Google Scholar] [CrossRef] [PubMed]
  317. Jiang, X.; Guo, S.; Xu, M.; Ma, B.; Liu, R.; Xu, Y.; Zhang, Y. TFAP2C-Mediated lncRNA PCAT1 Inhibits Ferroptosis in Docetaxel-Resistant Prostate Cancer Through c-Myc/miR-25-3p/SLC7A11 Signaling. Front. Oncol. 2022, 12, 862015. [Google Scholar] [CrossRef] [PubMed]
  318. Chen, Y.; Fang, Z.-M.; Yi, X.; Wei, X.; Jiang, D.-S. The Interaction between Ferroptosis and Inflammatory Signaling Pathways. Cell Death Dis. 2023, 14, 205. [Google Scholar] [CrossRef]
  319. Hu, X.; Li, J.; Fu, M.; Zhao, X.; Wang, W. The JAK/STAT Signaling Pathway: From Bench to Clinic. Signal Transduct. Target. Ther. 2021, 6, 402. [Google Scholar] [CrossRef]
  320. Hu, Q.; Bian, Q.; Rong, D.; Wang, L.; Song, J.; Huang, H.-S.; Zeng, J.; Mei, J.; Wang, P.-Y. JAK/STAT Pathway: Extracellular Signals, Diseases, Immunity, and Therapeutic Regimens. Front. Bioeng. Biotechnol. 2023, 11, 1110765. [Google Scholar] [CrossRef]
  321. Harrison, D.A. The JAK/STAT Pathway. Cold Spring Harb. Perspect. Biol. 2012, 4, a011205. [Google Scholar] [CrossRef]
  322. Tolomeo, M.; Cascio, A. The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy. Int. J. Mol. Sci. 2021, 22, 603. [Google Scholar] [CrossRef] [PubMed]
  323. Tsoi, J.; Robert, L.; Paraiso, K.; Galvan, C.; Sheu, K.M.; Lay, J.; Wong, D.J.L.; Atefi, M.; Shirazi, R.; Wang, X.; et al. Multi-Stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress. Cancer Cell 2018, 33, 890–904.e5. [Google Scholar] [CrossRef]
  324. Wang, W.; Green, M.; Choi, J.E.; Gijón, M.; Kennedy, P.D.; Johnson, J.K.; Liao, P.; Lang, X.; Kryczek, I.; Sell, A.; et al. CD8+ T Cells Regulate Tumour Ferroptosis during Cancer Immunotherapy. Nature 2019, 569, 270–274. [Google Scholar] [CrossRef] [PubMed]
  325. Yu, X.; Zhu, D.; Luo, B.; Kou, W.; Cheng, Y.; Zhu, Y. IFNγ Enhances Ferroptosis by Increasing JAK-STAT Pathway Activation to Suppress SLCA711 Expression in Adrenocortical Carcinoma. Oncol. Rep. 2022, 47, 97. [Google Scholar] [CrossRef]
  326. Kong, R.; Wang, N.; Han, W.; Bao, W.; Lu, J. IFNγ-Mediated Repression of System Xc− Drives Vulnerability to Induced Ferroptosis in Hepatocellular Carcinoma Cells. J. Leukoc. Biol. 2021, 110, 301–314. [Google Scholar] [CrossRef]
  327. Wei, T.; Zhang, M.; Zheng, X.; Xie, T.; Wang, W.; Zou, J.; Li, Y.; Li, H.; Cai, J.; Wang, X.; et al. Interferon-γ Induces Retinal Pigment Epithelial Cell Ferroptosis by a JAK1-2/STAT1/SLC7A11 Signaling Pathway in Age-related Macular Degeneration. FEBS J. 2022, 289, 1968–1983. [Google Scholar] [CrossRef]
  328. Gao, H.; Bai, Y.; Jia, Y.; Zhao, Y.; Kang, R.; Tang, D.; Dai, E. Ferroptosis Is a Lysosomal Cell Death Process. Biochem. Biophys. Res. Commun. 2018, 503, 1550–1556. [Google Scholar] [CrossRef] [PubMed]
  329. Ouyang, S.; Li, H.; Lou, L.; Huang, Q.; Zhang, Z.; Mo, J.; Li, M.; Lu, J.; Zhu, K.; Chu, Y.; et al. Inhibition of STAT3-Ferroptosis Negative Regulatory Axis Suppresses Tumor Growth and Alleviates Chemoresistance in Gastric Cancer. Redox Biol. 2022, 52, 102317. [Google Scholar] [CrossRef]
  330. Liu, Q.; Wang, K. The Induction of Ferroptosis by Impairing STAT3/Nrf2/GPx4 Signaling Enhances the Sensitivity of Osteosarcoma Cells to Cisplatin. Cell Biol. Int. 2019, 43, 1245–1256. [Google Scholar] [CrossRef]
  331. Luo, Y.; Gao, X.; Zou, L.; Lei, M.; Feng, J.; Hu, Z. Bavachin Induces Ferroptosis through the STAT3/P53/SLC7A11 Axis in Osteosarcoma Cells. Oxidative Med. Cell. Longev. 2021, 2021, 1783485. [Google Scholar] [CrossRef]
  332. Linher-Melville, K.; Haftchenary, S.; Gunning, P.; Singh, G. Signal Transducer and Activator of Transcription 3 and 5 Regulate System Xc- and Redox Balance in Human Breast Cancer Cells. Mol. Cell Biochem. 2015, 405, 205–221. [Google Scholar] [CrossRef] [PubMed]
  333. Sethi, G.; Sung, B.; Aggarwal, B.B. Nuclear Factor-kappaB Activation: From Bench to Bedside. Exp. Biol. Med. 2008, 233, 21–31. [Google Scholar] [CrossRef]
  334. Oeckinghaus, A.; Hayden, M.S.; Ghosh, S. Crosstalk in NF-κB Signaling Pathways. Nat. Immunol. 2011, 12, 695–708. [Google Scholar] [CrossRef] [PubMed]
  335. Liu, T.; Zhang, L.; Joo, D.; Sun, S.-C. NF-κB Signaling in Inflammation. Signal Transduct. Target. Ther. 2017, 2, 17023. [Google Scholar] [CrossRef] [PubMed]
  336. Kaltschmidt, B.; Kaltschmidt, C. NF-kappaB in the Nervous System. Cold Spring Harb. Perspect. Biol. 2009, 1, a001271. [Google Scholar] [CrossRef] [PubMed]
  337. Xia, L.; Tan, S.; Zhou, Y.; Lin, J.; Wang, H.; Oyang, L.; Tian, Y.; Liu, L.; Su, M.; Wang, H.; et al. Role of the NFκB-Signaling Pathway in Cancer. OTT 2018, 11, 2063–2073. [Google Scholar] [CrossRef]
  338. Zinatizadeh, M.R.; Schock, B.; Chalbatani, G.M.; Zarandi, P.K.; Jalali, S.A.; Miri, S.R. The Nuclear Factor Kappa B (NF-κB) Signaling in Cancer Development and Immune Diseases. Genes Dis. 2021, 8, 287–297. [Google Scholar] [CrossRef]
  339. Liu, G.-H.; Qu, J.; Shen, X. NF-κB/P65 Antagonizes Nrf2-ARE Pathway by Depriving CBP from Nrf2 and Facilitating Recruitment of HDAC3 to MafK. Biochim. Biophys. Acta (BBA)-Mol. Cell Res. 2008, 1783, 713–727. [Google Scholar] [CrossRef]
  340. Xu, M.; Tao, J.; Yang, Y.; Tan, S.; Liu, H.; Jiang, J.; Zheng, F.; Wu, B. Ferroptosis Involves in Intestinal Epithelial Cell Death in Ulcerative Colitis. Cell Death Dis. 2020, 11, 86. [Google Scholar] [CrossRef]
  341. Yan, N.; Xu, Z.; Qu, C.; Zhang, J. Dimethyl Fumarate Improves Cognitive Deficits in Chronic Cerebral Hypoperfusion Rats by Alleviating Inflammation, Oxidative Stress, and Ferroptosis via NRF2/ARE/NF-κB Signal Pathway. Int. Immunopharmacol. 2021, 98, 107844. [Google Scholar] [CrossRef]
  342. Li, S.; He, Y.; Chen, K.; Sun, J.; Zhang, L.; He, Y.; Yu, H.; Li, Q. RSL3 Drives Ferroptosis through NF-κB Pathway Activation and GPX4 Depletion in Glioblastoma. Oxidative Med. Cell. Longev. 2021, 2021, 2915019. [Google Scholar] [CrossRef]
  343. Schmitt, A.; Xu, W.; Bucher, P.; Grimm, M.; Konantz, M.; Horn, H.; Zapukhlyak, M.; Berning, P.; Brändle, M.; Jarboui, M.-A.; et al. Dimethyl Fumarate Induces Ferroptosis and Impairs NF-κB/STAT3 Signaling in DLBCL. Blood 2021, 138, 871–884. [Google Scholar] [CrossRef]
  344. Wang, Y.; Feng, J.; Zhao, L.; Zhao, M.; Wei, X.; Geng, Y.; Yuan, H.; Hou, C.; Zhang, H.; Wang, G.; et al. Aspirin Triggers Ferroptosis in Hepatocellular Carcinoma Cells through Restricting NF-κB P65-Activated SLC7A11 Transcription. Acta Pharmacol. Sin. 2023, 44, 1712–1724. [Google Scholar] [CrossRef]
  345. Jin, H.; Zhu, Z.; Yu, P.; Wang, G.; Zhang, J.; Li, J.; Ai, R.; Li, Z.; Tian, Y.; Xu, W.; et al. Myrislignan Attenuates Lipopolysaccharide-induced Inflammation Reaction in Murine Macrophage Cells Through Inhibition of NF-κB Signalling Pathway Activation. Phytother. Res. 2012, 26, 1320–1326. [Google Scholar] [CrossRef]
  346. Zhou, Y.; Qian, W.; Li, X.; Wei, W. NF-κB Inhibitor Myrislignan Induces Ferroptosis of Glioblastoma Cells via Regulating Epithelial-Mesenchymal Transformation in a Slug-Dependent Manner. Oxidative Med. Cell. Longev. 2023, 2023, 7098313. [Google Scholar] [CrossRef]
  347. Xiao, X.; Yeoh, B.S.; Vijay-Kumar, M. Lipocalin 2: An Emerging Player in Iron Homeostasis and Inflammation. Annu. Rev. Nutr. 2017, 37, 103–130. [Google Scholar] [CrossRef]
  348. Yao, F.; Deng, Y.; Zhao, Y.; Mei, Y.; Zhang, Y.; Liu, X.; Martinez, C.; Su, X.; Rosato, R.R.; Teng, H.; et al. A Targetable LIFR−NF-κB−LCN2 Axis Controls Liver Tumorigenesis and Vulnerability to Ferroptosis. Nat. Commun. 2021, 12, 7333. [Google Scholar] [CrossRef] [PubMed]
  349. Weinberg, R.L.; Freund, S.M.V.; Veprintsev, D.B.; Bycroft, M.; Fersht, A.R. Regulation of DNA Binding of P53 by Its C-Terminal Domain. J. Mol. Biol. 2004, 342, 801–811. [Google Scholar] [CrossRef] [PubMed]
  350. Grossman, S.R. P300/CBP/P53 Interaction and Regulation of the P53 Response. Eur. J. Biochem. 2001, 268, 2773–2778. [Google Scholar] [CrossRef] [PubMed]
  351. Pflaum, J.; Schlosser, S.; Müller, M. P53 Family and Cellular Stress Responses in Cancer. Front. Oncol. 2014, 4, 285. [Google Scholar] [CrossRef]
  352. Mallette, F.A.; Calabrese, V.; Ilangumaran, S.; Ferbeyre, G. SOCS1, a Novel Interaction Partner of P53 Controlling Oncogene-Induced Senescence. Aging 2010, 2, 445–452. [Google Scholar] [CrossRef] [PubMed]
  353. Saint-Germain, E.; Mignacca, L.; Vernier, M.; Bobbala, D.; Ilangumaran, S.; Ferbeyre, G. SOCS1 Regulates Senescence and Ferroptosis by Modulating the Expression of P53 Target Genes. Aging 2017, 9, 2137–2162. [Google Scholar] [CrossRef] [PubMed]
  354. Zhang, X.; Zheng, Q.; Yue, X.; Yuan, Z.; Ling, J.; Yuan, Y.; Liang, Y.; Sun, A.; Liu, Y.; Li, H.; et al. ZNF498 Promotes Hepatocellular Carcinogenesis by Suppressing P53-Mediated Apoptosis and Ferroptosis via the Attenuation of P53 Ser46 Phosphorylation. J. Exp. Clin. Cancer Res. 2022, 41, 79. [Google Scholar] [CrossRef] [PubMed]
  355. Jiang, L.; Kon, N.; Li, T.; Wang, S.-J.; Su, T.; Hibshoosh, H.; Baer, R.; Gu, W. Ferroptosis as a P53-Mediated Activity during Tumour Suppression. Nature 2015, 520, 57–62. [Google Scholar] [CrossRef]
  356. Zhang, Y.; Qian, Y.; Zhang, J.; Yan, W.; Jung, Y.-S.; Chen, M.; Huang, E.; Lloyd, K.; Duan, Y.; Wang, J.; et al. Ferredoxin Reductase Is Critical for P53-Dependent Tumor Suppression via Iron Regulatory Protein 2. Genes Dev. 2017, 31, 1243–1256. [Google Scholar] [CrossRef]
  357. Zhang, Z.; Guo, M.; Shen, M.; Kong, D.; Zhang, F.; Shao, J.; Tan, S.; Wang, S.; Chen, A.; Cao, P.; et al. The BRD7-P53-SLC25A28 Axis Regulates Ferroptosis in Hepatic Stellate Cells. Redox Biol. 2020, 36, 101619. [Google Scholar] [CrossRef]
  358. Ou, Y.; Wang, S.-J.; Li, D.; Chu, B.; Gu, W. Activation of SAT1 Engages Polyamine Metabolism with P53-Mediated Ferroptotic Responses. Proc. Natl. Acad. Sci. USA 2016, 113, E6806–E6812. [Google Scholar] [CrossRef]
  359. Chen, X.; Comish, P.B.; Tang, D.; Kang, R. Characteristics and Biomarkers of Ferroptosis. Front. Cell Dev. Biol. 2021, 9, 637162. [Google Scholar] [CrossRef]
  360. Ma, X.-H.; Liu, J.-H.-Z.; Liu, C.-Y.; Sun, W.-Y.; Duan, W.-J.; Wang, G.; Kurihara, H.; He, R.-R.; Li, Y.-F.; Chen, Y.; et al. ALOX15-Launched PUFA-Phospholipids Peroxidation Increases the Susceptibility of Ferroptosis in Ischemia-Induced Myocardial Damage. Signal Transduct. Target. Ther. 2022, 7, 288. [Google Scholar] [CrossRef]
  361. Fedorka, S.R.; So, K.; Al-Hamashi, A.A.; Gad, I.; Shah, R.; Kholodovych, V.; Alqahtani, H.D.; Taylor, W.R.; Tillekeratne, L.M.V. Small-Molecule Anticancer Agents Kill Cancer Cells by Harnessing Reactive Oxygen Species in an Iron-Dependent Manner. Org. Biomol. Chem. 2018, 16, 1465–1479. [Google Scholar] [CrossRef] [PubMed]
  362. Kuganesan, N.; Dlamini, S.; Tillekeratne, L.M.V.; Taylor, W.R. Tumor Suppressor P53 Promotes Ferroptosis in Oxidative Stress Conditions Independent of Modulation of Ferroptosis by P21, CDKs, RB, and E2F. J. Biol. Chem. 2021, 297, 101365. [Google Scholar] [CrossRef] [PubMed]
  363. Venkatesh, D.; Stockwell, B.R.; Prives, C. P21 Can Be a Barrier to Ferroptosis Independent of P53. Aging 2020, 12, 17800–17814. [Google Scholar] [CrossRef] [PubMed]
  364. Zheng, Z.; Shang, X.; Sun, K.; Hou, Y.; Zhang, X.; Xu, J.; Liu, H.; Ruan, Z.; Hou, L.; Guo, Z.; et al. P21 Resists Ferroptosis in Osteoarthritic Chondrocytes by Regulating GPX4 Protein Stability. Free. Radic. Biol. Med. 2024, 212, 336–348. [Google Scholar] [CrossRef]
  365. Tarangelo, A.; Magtanong, L.; Bieging-Rolett, K.T.; Li, Y.; Ye, J.; Attardi, L.D.; Dixon, S.J. P53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells. Cell Rep. 2018, 22, 569–575. [Google Scholar] [CrossRef]
  366. Johnson, T.M.; Hammond, E.M.; Giaccia, A.; Attardi, L.D. The p53QS Transactivation-Deficient Mutant Shows Stress-Specific Apoptotic Activity and Induces Embryonic Lethality. Nat. Genet. 2005, 37, 145–152. [Google Scholar] [CrossRef]
  367. Chen, W.; Sun, Z.; Wang, X.-J.; Jiang, T.; Huang, Z.; Fang, D.; Zhang, D.D. Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response. Mol. Cell 2009, 34, 663–673. [Google Scholar] [CrossRef]
  368. Tarangelo, A.; Dixon, S. The P53-P21 Pathway Inhibits Ferroptosis during Metabolic Stress. Oncotarget 2018, 9, 24572–24573. [Google Scholar] [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Article Metrics

Citations

Article Access Statistics

Journal Statistics
Multiple requests from the same IP address are counted as one view.
Download PDF
Identification of Oxidative-Stress-Reducing Plant Extracts from a Novel Extract Library—Comparative Analysis of Cell-Free and Cell-Based In Vitro Assays to Quantitate Antioxidant Activity
Previous
Insight into the Antioxidant Activity of Ascorbic Acid-Containing Gelatin Nanoparticles in Simulated Chronic Wound Conditions
Next