Next Article in Journal
Genome-Wide Identification and Expression Pattern Profiling of the Aquaporin Gene Family in Papaya (Carica papaya L.)
Next Article in Special Issue
Glycyrol Prevents the Progression of Psoriasis-like Skin Inflammation via Immunosuppressive and Anti-Inflammatory Actions
Previous Article in Journal
Paracrine Responses of Cardiosphere-Derived Cells to Cytokines and TLR Ligands: A Comparative Analysis
Previous Article in Special Issue
Exploring the Anti-Osteoporotic Potential of Daucosterol: Impact on Osteoclast and Osteoblast Activities
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Ferroptosis: Emerging Role in Diseases and Potential Implication of Bioactive Compounds

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(24), 17279;
Submission received: 27 October 2023 / Revised: 1 December 2023 / Accepted: 7 December 2023 / Published: 8 December 2023


Ferroptosis is a form of cell death that is distinguished from other types of death for its peculiar characteristics of death regulated by iron accumulation, increase in ROS, and lipid peroxidation. In the past few years, experimental evidence has correlated ferroptosis with various pathological processes including neurodegenerative and cardiovascular diseases. Ferroptosis also is involved in several types of cancer because it has been shown to induce tumor cell death. In particular, the pharmacological induction of ferroptosis, contributing to the inhibition of the proliferative process, provides new ideas for the pharmacological treatment of cancer. Emerging evidence suggests that certain mechanisms including the Xc system, GPx4, and iron chelators play a key role in the regulation of ferroptosis and can be used to block the progression of many diseases. This review summarizes current knowledge on the mechanism of ferroptosis and the latest advances in its multiple regulatory pathways, underlining ferroptosis’ involvement in the diseases. Finally, we focused on several types of ferroptosis inducers and inhibitors, evaluating their impact on the cell death principal targets to provide new perspectives in the treatment of the diseases and a potential pharmacological development of new clinical therapies.

1. Introduction

Cell death is a physiological end-of-life process generally caused by irreversible damage. In general, two distinct types of cell death can be distinguished: accidental cell death and regulated cell death. Regulated cell death relies on specialized molecular mechanisms and can be delayed or accelerated. A normal cell is limited to a defined range of functions established by its genetic program. When the cell is no longer able to respond to physiological demands, an irreversible process of cell death begins. There are different types of cell death, characterized by the different pathways involved: the best known are necrosis and apoptosis. The first caused by physical or chemical damage of an external nature; the second, called cell suicide, occurs during development and morphogenesis. Among other types of cell death, autophagy is a catabolic process of the selective degradation of damaged organelles and macromolecules by lysosomes, while ferroptosis is a type of iron-dependent cell death caused by oxidative-mediated phospholipid damage, which has been recently discovered [1].
Study of the cell death process is important because it represents one of the potential pharmacological points of intervention to avoid the onset of some pathological events and to facilitate the development of therapeutic strategies. In this context, evidence suggests ferroptosis as one of the main cell death mechanisms promoting degenerative diseases, but contextually this process seems to be a new hope for many cancer therapies. In the past decade, the great bioactive potential of natural compounds against ferroptosis has been affirmed. In this review, the mechanism of ferroptosis and its involvement in some of the main diseases affecting human health will be highlighted by evaluating the role of some inducers and inhibitors in the cell death process.

2. Ferroptosis: An Overview

Ferroptosis is an iron-dependent programmed cell death that was first identified by Dr. Brent R. Stockwell and described by Dixon in 2012. The main signal of the process is iron accumulation, an increase in oxygen reactive species (ROS), and lipid peroxidation (see Table 1) [2,3].
From a morphological point of view, ferroptosis is mainly manifested by the narrowing of mitochondria (shrinkage), an increase in membrane density, and a reduction in mitochondrial cristae, followed by rupture of the outer membrane (see Table 1) [2,4]. Ferroptosis biological processes mainly include altered iron homeostasis leading to intracellular accumulation of Fe2+, decrease in reduced glutathione (GSH) and consequent decreased activity of Glutathione peroxidase 4 (GPx4), increase in radical species, and lipid peroxidation. Interestingly, oxidative stress and lipid peroxidation, two of the main features of ferroptosis, are also two key processes in cancer immunotherapy. This is an emerging treatment that functions to modulate the activity of immune cells, activating them against the processes of carcinogenesis; thus, this therapy does not act directly on the tumor but acts in modulating the immune system. Studies have shown that T lymphocytes activated during therapy increase lipid peroxidation, thus leading to oxidative stress, a mechanism underlying ferroptosis. Wang et al. in their study saw how CD8+ T cells, involved in neutralizing tumor cells, release proinflammatory cytokines, such as tumor necrosis factor (TNF) and gamma interferon. These molecules inhibit the expression of Solute Carrier Family 7 Member 11 (SLC7A11) and Solute Carrier Family 3 Member 2 (SLC3A2), two subunits of the xc system, and further direct the target (tumor) cell toward ferroptosis. The study carried out by the scholars thus provides insight into how ferroptosis could be induced within the body as a defense tool against the processes of carcinogenesis [2,5,6] Ferroptosis may be closely linked to the pathogenesis of various conditions including aging, neurodegenerative diseases, cardiovascular diseases, metabolic diseases, and autoimmune diseases [7,8,9,10]. For example, in Parkinson’s disease, iron accumulation in dopaminergic neurons can lead to ferroptosis and neuronal death. Other neurodegenerative diseases in which a correlation with ferroptosis has been observed are Alzheimer’s disease (AD), Huntington’s disease (HD), and Amyotrophic lateral sclerosis (ALS), which are pathologies that we will discuss in more detail in the following paragraphs. In addition, it has been suggested that ferroptosis may play a role in ischemia/reperfusion injury, where the accumulation of iron and subsequent lipid peroxidation contribute to tissue damage [11]. Ferroptosis can also be used against cancer cells; in fact, one of the main and more dangerous features of cancer cells is escape from cell death. Several studies have demonstrated that ferroptosis induction can inhibit the proliferation of tumor cells, providing new promising therapeutic strategies for cancer treatment [12,13,14,15,16]. Induction of ferroptosis could be useful both in determining the death of cells resistant to classic anticancer treatments and as an adjunct to classic therapies. Indeed, it has been seen in a study by Roh J.L. et al. that ferroptotic inducers, such as cisplatin, can adjunct the action of classic anticancer drugs by inhibiting tumor cell proliferation in mouse models [17]. In addition, in a work conducted by Chen X. et al. it was seen that the induction of ferroptosis for cancer therapy is closely related to the type of cancer we consider. In fact, some cancers such as melanoma, breast cancer, etc., which are characterized by iron accumulation, elevated fatty acid synthesis, increased autophagic processes, and the EMT mechanism (epithelial-mesenchymal transition, leads epithelial cells to conversion to mesenchymal cells), are more susceptible to ferroptosis, making possible the application of this strategy [18]. In summary, ferroptosis is a complex process characterized by multiple factors including iron accumulation, oxidative stress, and inflammation, and it is involved in the genesis of a wide spectrum of serious diseases that are still not effectively controlled and eradicated. Study of the molecular mechanisms and signaling pathways of ferroptosis, although very complex, can contribute to opening new therapeutic opportunities. It has already been shown that ferroptosis can be pharmacologically inhibited with iron chelators, such as deferoxamine, and lipid peroxidation inhibitors such as ferrostatin [19]. Ferroptosis can instead be induced by mutations of RAS, which may cause iron accumulation following activation of transferrin receptor 1 (TfR1) and suppression of iron storage proteins [19,20].

3. Mechanism of Ferroptosis

Although the complexities of the molecular processes involved in Ferroptosis are still not enough described and fully understood, the main biological pathways and regulatory factors are iron homeostasis, lipid metabolism, and antioxidant defense systems (see Figure 1) [3].

3.1. Iron Homeostasis

Iron is an essential trace metal in the body, where it may exist in two oxidation states: ferrous iron (Fe2+) and ferric iron (Fe3+). Iron may take or lose electrons; in a Fenton reaction, ferrous iron gives an electron to hydrogen peroxide (H2O2) to form hydroxyl radical (OH), a high reactive free radical [21]. The majority of iron ions are bound to iron-binding proteins and biomolecules that exploit its reactivity, limiting damage. Iron is bound to the active site of numerous enzymes, including Catalase, Aconitase, Succinate dehydrogenase, Cytochrome P450, Peroxidases, etc. [22]. Iron also plays a key role in several biochemical processes including deoxyribonucleic acid (DNA) synthesis, electron transport for ATP synthesis, and oxygen transport to tissues [23]. Despite its biochemical use, a disorder in the distribution and content of the body free iron could disrupt cell survival itself. In the Fenton reaction Fe2+ + HOOH → Fe3+ + OH + OH, iron salts react with peroxides to give highly harmful hydroxy radicals; this means that the intracellular free iron levels must be kept in a very narrow range [24]. Normally, excess Fe2+ ions are bound to the highly conserved iron-binding protein ferritin, which is an intracellular protein with ferroxidase activity that stores ferrous iron (Fe2+), converting it to ferric (Fe3+) forms [22]. When the body needs iron, ferritin releases the metal that reaches the bloodstream via ferroportin; ferroportin and divalent metal transporter 1 (DMT1) are the two main iron transmembrane transporters: an extracellular exporter and an intracellular importer, respectively. In the blood, iron circulates bound to transferrin (Tf), which is a glycoprotein consisting of a single polypeptide chain that possesses two binding sites for the ferric ion (Fe3+). Tf delivers Fe3+ ions to various tissues after binding to its specific receptor (TfR) on the cell surface. The importance of iron in many biochemical processes and its high hazard linked to the Fenton reaction make a constant balance between metal uptake, transport, storage, and utilization to maintain iron homeostasis extremely important [25]. The main proteins regulating iron homeostasis are hepcidin, which regulates the flow of iron from cells into the systemic circulation, and iron regulatory proteins (IRP1 and 2) that mediate regulation of intracellular iron homeostasis [26]. Dysregulation of IRP1 and/or IRP2 can lead to iron level changes and ferroptosis regulation [27]. Ferroptosis can be prevented or possibly also induced by iron chelating agents including deferoxamine, deferiprone, and deferasirox which, by chelating to iron, reduce its availability [2,27]. Generally, all regulators of iron metabolism may be involved in the regulation of ferroptosis as well as ferritinophagy, a selective form of autophagy which may contribute to the onset of ferroptosis through ferritin degradation [28]. Specifically, ferritinophagy is mediated by nuclear receptor coactivator 4 (NCOA4), a selective cargo receptor which binds microtubule-associated proteins to the developing autophagosome membrane [29]. NCOA4 levels, in turn, are modulated by cellular iron levels in a way that high iron pressure decreases NCOA4-E3 ubiquitin–protein ligase HERC2 binding, avoiding elevated NCOA4 degradation through the ubiquitin proteasome system when the cellular iron levels are high [30]. Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron-dependent HERC2-mediated proteolysis [31]. These findings highlight NCOA4 and HERC2 as further potential regulators of ferroptosis. An increase in NCOA4 leads to ferritin degradation and intracellular ferrous iron increase, triggering ferroptosis, while the knockdown of NCOA4 levels blocks ferritin degradation, also suppressing erastin-induced ferroptosis in pancreatic cells [32]. Loss of coatomer subunit zeta-1 (COPZ1) induces NCOA4-mediated autophagy and ferroptosis in glioblastoma cell lines [33].

3.2. Lipid Metabolism

Unlike many other programmed cell deaths, ferroptosis is characterized by high levels of lipid peroxidation. The cell membrane is principally constituted of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin, which together account for more than half of the total lipid. In addition, phospholipids, cholesterol, and glycoprotein are found; among them, polyunsaturated fatty acids (PUFAs) are the most susceptible to peroxidation. Normally, long-chain-PUFAs are converted in PUFA-CoA by Acyl-CoA synthase long-chain family member 4 (ACSL4) to facilitate their entry into the phospholipid bilayer [34]. In the peroxidation process, membrane-bound lipids containing PUFAs are mainly attacked because of the existence of a diallyl matrix that makes them highly susceptible to free radicals and lipoxygenases (LOXs). LOXs are iron-containing enzymes which catalyze the enzymatical lipid peroxidation chain, one of the main characteristics of ferroptosis. LOXs’ action oxidizes PUFAs, generating the corresponding hydroperoxide derivatives which, in turn, generate more aldehydes including 4-hydroxynonenal and malondialdehyde, triggering a dangerous chain reaction on the phospholipid bilayer that ultimately destructs the membrane’s integrity [7]. Another mechanism of lipid peroxidation involved in ferroptosis occurs by spontaneous non-enzymatic autoxidation. In this case, the oxidation trigger is an abnormal accumulation of free ferrous iron that through the Fenton reaction reacts with hydrogen peroxide-generating ferric iron and hydroxyl radicals [35]. The latter, highly unstable, damages the membrane by initiating the process of lipid peroxidation by extracting hydrogen from lipids containing carbon–carbon double bonds, especially from PUFAs [36]. Membrane oxidative damage is the final step of ferroptosis [37].

3.3. Antioxidant Defense Systems

The human body is equipped with a variety of antioxidant agents to counteract the dangerous action of oxidants and free radicals. In general, these can be divided in enzymatic and non-enzymatic antioxidants. The major enzymatic antioxidants are superoxide dismutase (SOD), catalase, and GPx. Among the intracellular antioxidant elements, the system Xc plays an important role. The system Xc is a glutamate–cystine antiport that takes cystine from outside the cell and excretes glutamate in a 1:1 ratio [38,39]. The system Xc⁻ is part of the heterodimeric amino acid transport family; the system widely distributed on cell membranes is composed of two subunits: a light chain SLC7A11, responsible for amino acid exchange, linked by a disulfide bridge to a heavy chain SLC3A2 which is a chaperone [38,40]. Inside the cell, cystine reductase reduces imported cystine to cysteine, which is then involved, with glycine and glutamate, in GSH biosynthesis, a key non-enzymatic player in cellular antioxidant defense. Cysteine availability is the rate-limiting amino acid for GSH synthesis; therefore, cysteine uptake mediated by system Xc is important to maintain cell redox homeostasis [41,42]. Specifically, the importance of GSH is due to its thiol group; the compound is a cofactor of glutathione peroxidase (GPx) [3]. In mammals, eight GPx1-8 are known. In most cases, GPx are selenoproteins, except for GPx 5,7,8 and GPx6 in rodents [43,44]. GPx catalyzes the reduction in hydroperoxides (e.g., H2O2) in H2O, but also lipid peroxides (LOOH) into their respective alcohols via oxidation of reduced GSH into its disulfide form (GSSG). Specifically, GPx4 is recognized as a key mediator of a variety of human diseases, including the regulation of ferroptosis [45]. The depletion of GSH or GPx4 causes an increase in lipid peroxides that damage the cell membrane and lead to ferroptotic cell death. In fact, the presence of GSH allows a rapid intracellular degradation of hydroxides that inhibits the generation of lipid ROS; in addition, it has been shown that the use of a GPx4 activator can reduce ROS and inhibit ferroptosis [46,47]. It should be outlined that among the three different GPx4 isoforms, a cytosolic, a mitochondrial, and a nuclear one, only the cytosolic possesses these abilities. Probably, ferroptosis inhibition by GPx4 is linked to the cytosolic dislocation of the protein, which allows it to catalyze the reduction in complex hydroxides such as phospholipid and cholesterol hydroperoxides, protecting the membrane from the chain of lipid peroxidation reactions that could lead to ferroptosis [48]. In addition to System Xc, cells use a minor player to produce cysteine: the transsulfuration pathway. Cysteine through this pathway can be synthesized using methionine as a precursor from which to take sulfur atoms and transfer them to serine [49]. This process may represent a compensating pathway to avoid the loss of cysteine import when the system Xc-GPx4 pathway is inhibited, and in the same way, it may be considered an alternative antioxidant defense. Other than these antioxidant systems, ferroptosis may be regulated by independent pathways such as FSP1/CoQ10, DHODH/CoQ10, and GCH1/BH4. In particular, the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2), renamed as ferroptosis suppressor protein 1 (FSP1), is a CoQ10 redox enzyme dependent on nicotinamide adenine dinucleotide phosphate (NADP) [50]. FSP1 acts on ferroptosis through a mechanism mediated by ubiquinone or coenzyme Q10 (CoQ10). The reduced form of CoQ10, ubiquinol (CoQH2), is a lipophilic free radical trapping agent which traps peroxyl radicals and limiting lipid peroxidation, whereas FSP1 catalyzes the regeneration of CoQ10 using NAD(P)H [51]. In this way, FSP1/CoQ10 may be considered as a stand-alone parallel pathway, which co-operates with GPx4 and GSH to suppress ferroptosis [52]. A further support to this system is given by dihydroorotate dehydrogenase (DHODH), a flavin-dependent enzyme which, in the mitochondrial membrane, catalyzes the oxidation of dihydroorotate (DHO) to orotate (OA) in the pyrimidine synthesis pathway (essential for RNA/DNA synthesis) [53]. In this reaction, CoQ10 acting as an electron acceptor from DHODH and complexes I and II is reduced to ubiquinol (CoQH2) and transports electrons to complex III. Therefore, there is a synergistical action between DHODH and FSP1 involving the conversion of CoQ10 to CoQH2 which affects ROS content and improves mitochondrial functionality [54,55]. The action of DHODH restores peroxide-damaged mitochondrial lipids and inhibits ferroptosis machinery [56]. Recent studies describe the GCH1/BH4 pathway as an endogenous antioxidant enzyme system that acting independently from GPx4/GSH inhibits ferroptosis [57]. Tetrahydrobiopterin (BH4) is a cofactor involved in the redox reaction, and in the metabolism of aromatic amino acids, neurotransmitters, and nitric oxide, it plays many physiological roles including the regulation of oxidative stress and inflammation [58,59]. Its synthesis is regulated by GTP cyclohydrolase I (GCH1) [60]. BH4 is also a potent radical-trapping antioxidant, and its action is important in cases of GPx4 inhibition to protect lipid membranes from autoxidation. Hu et al. (2022) demonstrated that GCH1/BH4 inhibition causes a dangerous increase in free irons and ferritinophagy activation [61], while GCH1 overexpression reduces lipid peroxidation and protects against the ferroptosis process [62,63].

Erythroid Nuclear Factor 2-Related Factor and p53

Nuclear factor erythroid 2-related factor (Nrf2) is an antioxidant agent whose action may contribute to the onset of ferroptosis. In normal conditions, Nrf2 is bound to Kelchlike ECH-associated protein 1 (Keap1) in the cytoplasm; when the cell oxidative status is altered and oxidative stress increases, Nrf2 detaches by Keap1 and translocases in the nucleus. In the nucleus, Nrf2 interacts with the antioxidant response elements (ARE) mediating transcriptional activation of its responsive genes and modulating in vivo defense mechanisms against oxidative damage [64]. In detail, Nrf2 activity counteracts the increased ROS production in the mitochondria and influences mitochondrial biogenesis by maintaining the levels of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1α, as well as by promoting purine nucleotide biosynthesis [65,66]. Furthermore, Nrf2 promotes GSH biosynthesis and NADPH regeneration, which are both essential to optimize GPx4 function, and regulates iron and lipid metabolism, both implicated in the ferroptosis process [67,68]. On the other hand, the p53 protein is a transcription factor mainly known as a tumor suppressor. Under physiological conditions, p53 protein levels are maintained by rapid degradation through ubiquitin-dependent proteolysis, but in response to stress signals, p53 becomes resistant to MDM2-mediated degradation and rapidly accumulates in the cell [69]. Inhibition of p53 degradation and its stabilization induces several transcriptional programs in stressed cells, including cell cycle arrest and apoptosis [70,71]. In detail, MDM2 proteins act as ubiquitin ligase shuttles which transport p53 from the nucleus to the cytoplasm, where p53 degradation takes place [72,73]. Recently, intriguing features correlate p53 activation with ferroptosis regulation, as activation of p53 significantly reduces the expression of SLC7A11 in cells [74,75]. In the cell, inhibition of SLC7A11 expression by p53 causes a decreased activity of the system Xc which, in turn, leads to decreased GSH biosynthesis and indirectly GPx4 inhibition. All these features lead the cell to an oxidative imbalance with increased lipid peroxidation culminating in ferroptosis induction [76]. However, activation of p53 may also modulate the ferroptosis process by enhancing the expression of diamine acetyltransferase 1 (SAT1) and the mitochondrial glutaminase GLS2, which are important regulators in polyamine and glutamine metabolism, respectively [77,78]. Furthermore, p53 may suppress ferroptosis, targeting the inhibition of dipeptidyl peptidase 4 (DPP4) activity or by the induction of cyclin-dependent kinase inhibitor 1A (CDKN1A/p21) expression [79]. Although these results highlight the multifunctionality of p53 that makes this protein a crucial regulatory point, a better understanding of the mechanisms by which p53 controls ferroptosis is needed.

4. Ferroptosis Implication in Diseases

As already mentioned, ferroptosis may have different physiological and biochemical functions within our body; it plays a beneficial role in maintaining normal physiological functions of the body as it allows the removal of damaged cells. However, ferroptosis can also result in the death of undamaged cells, triggering the progressive development of different diseases, including cardiovascular diseases, neurodegenerative diseases, and cancer (see Figure 2) [80].

4.1. Cancer

Cancer is a multifactorial disease that is widespread throughout the world despite significant efforts and notable improvements in the healthcare field. Overall, there are two significant challenges in treating the disease. The first concerns how to effectively kill tumor cells without harming healthy cells and the second is related to the ability of tumor cells, in the advanced stage of the disease, to resist pharmaceutical treatments [81]. One of the most popular strategies in the treatment of the disease is related to the activation of the apoptotic pathway, which results in the death of tumor and non-tumor cells. However, activation of the pathway is not always possible because cancer cells are mutated cells, and they can be resistant to certain drugs that trigger this pathway [82]. In this context, it is important to emphasize the existence of several forms of cell death because it is possible that drug-resistant cancer cells may be more susceptible to other types of cell death, including ferroptosis. The latter proves to be efficient against various types of chemo-resistant tumor cells that have escaped pharmacological treatment or are in an advanced pathological state [83]. Induced ferroptosis, in chemotherapy treatment, can be intended either as monotherapy or to improve the activity of other tumor drugs. Erastin (classic inducer of ferroptosis), for example, can increase the activity of classic tumor drugs such as temozolomide and cisplatin [84,85]. Therefore, a reduction in targets of Nrf2 (an upstream transcriptional regulator of SLC7A11 and GPx4) makes cells susceptible to the activity of proferroptotic agents in some types of cancer [86]. Different studies have shown that proferroptotic compounds target key elements of iron metabolism, such as the Xc and GPx4 systems, causing iron dyshomeostasis and triggering ferroptosis, leading cancer cells to their death. In particular, the reduced expression of genes, which encode for Xc system proteins, such as SLC7A11 and SLC3A2 causes the increase in ROS-mediated lipid peroxidation and subsequent ferroptosis, even in tumor cells that are more resistant to drug treatments [17,87]. In addition, another critical mediator of the proferroptotic cascade is acyl coenzyme A synthase long-chain member 4 (ACSL4); this enzyme, belonging to the ACL family, preferentially catalyzes the conversion of PUFAs, such as arachidonic acid, into fatty acyl-CoA esters. The catalytic activity of ACSL4 enriches the phospholipid bilayer of the cellular membrane with long unsaturated fatty acid, the main target of lipid peroxidation by ferroptosis [88]. Some studies highlighted a correlation between ACSL4 expression and cancer aggressiveness and proliferation [89,90,91]; subjects with colorectal cancer with a high expression of ACSL4 have a poor prognosis and lower survival rate, while subjects with brain, breast, or lung cancer with lower ACSL4 expression have a more hopeful prognosis [91]. Several studies also tested the connection of ferroptosis with immunotherapy and radiotherapy in cellular cancer death. In detail, immunotherapy results in the activation of the antitumor immune response activated by cytotoxic T cells. Interferon gamma (IFN-γ) released by CD8 T cells can hinder the uptake of cystine by tumor cells as it results in under regulation of the expression of SLC3A2 and SLC7A11 (subunits of the system Xc) and thus induces lipid peroxidation and ferroptosis in ovarian carcinoma, melanoma, and fibrosarcoma [5,92]. On the other hand, radiotherapy is a common modality of cancer treatment in which targeted delivery of ionizing radiation is used to eradicate cancer cells. Ionizing radiation induces DNA damage and stimulates ROS generation, provoking a high lipid peroxidation state, which is one of the main ferroptosis features.
Indeed, biochemical evidence correlates ferroptosis with cancer radiotherapy, which results in ACSL4 expression triggering PUFA peroxidation and ferroptosis in different tumors, including melanoma and esophageal cancer [93,94]. Collectively, several studies support the key role of ferroptosis and lipid peroxidation in preclinical and clinical settings to enhance and potentiate the effectiveness of chemotherapy drugs. However, further studies are needed to better elucidate this synergistic mechanism and to explore the many key regulations of ferroptosis.

4.2. Neurological Diseases

Neurological disorders are the leading cause of disability in the world; and they include a wide variety of pathological conditions; the most known are Alzheimer’s (AD), Parkinson’s (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). A common feature of neurodegenerations is an accumulation of altered proteins and progressive loss of neurons. This condition is generally related to an inflammatory local state due to iron accumulation, oxidative stress, and lipid peroxidation. Furthermore, high oxygen consumption makes the brain, rich in PUFAs, particularly vulnerable to triggering the ferroptosis process [95,96].

4.2.1. Alzheimer’s Disease

Alzheimer’s disease (AD) is a widespread neurodegenerative disease generally characterized by extracellular amyloid protein deposition and intracellular neurofibrillary tangles due to hyperphosphorylation of the tau protein. These features cause a reduction in neurogenesis, neuronal death, and loss of synaptic connections. Scientific evidence has shown iron accumulation in the brain of patients with AD, positively correlated with disease progression and cognitive decline [97,98]. In AD brains, the imbalance of iron homeostasis is closely related to amyloid plaques and neurofibrillary tangles [99]. Iron deposition seems to colocalize in areas of the brain where neurofibrillary tangles are found, and this condition is associated with the progression of neurodegeneration [100]. Increased lipid peroxidation and abnormal iron accumulation in AD brains are the two trigger conditions of ferroptosis [101]. In AD mice with a GPx4 deficiency, it has been demonstrated that ferroptosis inhibitors improve the condition of neurodegeneration by blocking excessive iron accumulation and lipid peroxidation, thus reducing oxidative stress and inflammation [102,103]. Recent in vivo measurements of the brain and blood GSH in AD have revealed decreased GSH levels [104]. Furthermore, AD is characterized by iron dyshomeostasis, an altered expression of the Xc system, and by increased lipid oxidation, suggesting that therapies targeting ferroptosis may be potentially beneficial [105]. This suggests that regulation of iron metabolism and reduction in neuronal ferroptosis, with ferroptosis inhibitors, may be a promising therapeutic approach. Among the molecules involved in this mechanism, deferoxamine (DFO) is a synthetic iron chelator and is commonly used in the clinical setting; however, it is important to note that it shows 50% efficacy and fails to cross the blood–brain barrier. Another compound used in the treatment of the condition is deferiprone (DFP). This, like the previously mentioned molecule, is a synthetic compound that acts as an iron chelator. Compared with DFO, DFP shows greater efficacy and a safer therapeutic profile; in addition, this compound appears to be able to cross the blood–brain barrier. Quinoline and its derivates are also iron chelators [106]. These molecules, from studies conducted in animal models by Grossi et al., and Crounch et al., appear to induce an improvement in cognitive function and result in a reduction in the accumulation of Aβ by determining its degradation [107,108]. In addition, studies conducted by Wang et al. demonstrated that clioquinol results in a reduction in the expression of secretase β and γ and amyloid precursor protein (APP), while Lin et al. proved the ability to reduce tau protein tangles via tau degradation [109,110]. In addition to the previously mentioned molecules, another compound that can inhibit the ferroptotic process in AD is hepcidin. This can reduce the transport of iron across the blood–brain barrier, thus inhibiting its accumulation. In a study conducted by Du et al., 2015, it was seen that this compound in microvascular endothelial cells significantly inhibits the expression of FPN1, TfR1, and DMT1, can regulate iron homeostasis at the neuronal level, reducing iron uptake and release, and can also reduce Aβ plaque formation by increasing cognitive activity in the mouse models used in the study [111,112].

4.2.2. Parkinson’s Disease

Parkinson’s disease (PD) is manifested by muscle rigidity, tremors, even during rest, difficulty in starting or finishing movements, and balance disorders. The two main pathological features of PD are progressive dopaminergic neurodegeneration in the substantia nigra and misfolded a-synuclein, the major protein component of Lewy bodies. Scientific studies have highlighted the connection between the progression of PD and iron homeostasis in the brain tissue, showing common features with ferroptosis related to increased ROS generation, GSH depletion, and lipid peroxidation, which lead to the accumulation of malondialdehyde, a toxic subproduct [113,114]. Iron ion accumulation is correlated with an increased risk of the formation of α-synuclein fibers because of iron ions’ high affinity for α-synuclein. Iron accelerates the deposition of the misfolded protein, contributing to PD degeneration [115]. Furthermore, increased lipid peroxidation due to iron accumulation in the cell leads to damage of dopaminergic neurons, decreased dopamine production, and disruption of the neuron’s integrity [116]. In t-BHP-induced PC12 cells, used as a model of PD, a decrease in GPx4 expression, reduction in the GSH/GSSG ratio, and increase in lipid peroxidation were found; the harmful condition was reversed by ferrostatin-1 and deferoxamine, indicating an iron dependence of the process [117,118]. In this context, chelating agents are very important in pharmacological treatment for neuroprotection because iron chelation preventing Fe entrance in the Haber–Weiss reaction reduces ROS formation and oxidative stress [116,119,120]. An important chelating agent is DFP, which shows neuroprotective activity in patients with early-stage Parkinson’s disease [119]. In addition to this molecule, it was observed by Billings et al., in a study in transgenic PD mouse models, that clioquinol has the ability, as an iron chelator, to reduce the loss of neurons from the substance nigra, thereby protecting neurons from iron accumulation and inhibiting ferroptotic processes [120].

4.2.3. Huntington’s Disease

Huntington’s disease (HD) is a very rare disease that affects the central nervous system and is characterized by short and sudden involuntary movements, psychiatric disorders, dementia, and behavioral disorders. It is an autosomal dominant disorder caused by an abnormal repeat of a sequence of three DNA bases, cytosine–adenine–guanine (CAG) expansion in the huntingtin gene on chromosome 4. The mutated gene encodes an expanded polyglutamine stretch in the Huntington protein (Htt); longer CAG repeats are the cause of earlier onset and more severe symptoms in patients [121,122]. Mutant Htt protein accumulation is the trigger for pathological progression of the disease because of its aggregation tendency to form macromolecules, which leads to neuronal death. Cytoplasmic and nuclear toxic fragments cause mitochondrial dysfunction and increase ROS generation [123]. This status is worsened by lower GSH and GSH-S transferase levels detected in HD brains that cause an imbalance between antioxidant defenses and pro-oxidant conditions, increasing oxidative stress [124]. As a result, high lipid peroxidation is one of the main features in HD patients and increased formation of lipid peroxides colocalized with mutant Htt protein inclusions in HD mouse models has been detected [125,126]. In a recent article, Song et al. indicated arachidonate 5-lipoxygenase (ALOX5) as a mediator for the ACSL4 ferroptosis process in HD [127]. ALOX5 is a member of the lipoxygenase family, which metabolize arachidonic acid as well as PUFAs and contribute to lipid peroxidation [128]. In HD mice, the loss of ALOX5, by inactivation of Alox5 gene, ameliorated their pathological phenotypes, extending the life spans [113]. Iron dysmetabolism and accumulation is another characteristic in HD patients and a pivotal trigger of ferroptosis [129,130,131,132]. The implication of ferroptosis in HD is also supported by the positive action of iron chelators. Chen et al. demonstrated in R6/2 HD mice that intraventricular administration of deferoxamine improved the striatum pathology and motor phenotype [131]. Inhibitors of ferroptosis, such as ferrostatin-1 and liproxstatin-1, are also very important in the treatment of HD; they act by inhibiting damage caused by lipid peroxidation, thereby preserving healthy neurons [80]. The activity of Fer-1 was demonstrated through a study conducted by Skouta et al., where it was seen that treatment with Fer-1, at different concentrations of 10 nM, 100 nM and 1 μM, protects neurons from degeneration; in the same study conducted in MH cell models, it was seen how the molecule counteracts lipid peroxidation [133]. Another molecule that would seem to have effects in HD is DFO. A study conducted by Yang et al., in murine models of MH, demonstrated the protective activity of this compound, also improving the cognitive ability of the study models [134].

4.2.4. Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by selective degeneration of motor neurons in the brain and spinal cord. The disease leads to a slow but progressive decrease in the ability to perform voluntary movements and to progressive paralysis [135]. Despite fervent studies on ALS, to date the mechanism related to the onset of the disease remains partly obscure. Several genes have been identified as possible causes of ALS onset, including mutations in the gene for Cu, Zn superoxide dismutase 1 (SOD1) responsible for 20–40% of ALS familial forms [136]. Recently, a correlation has been discovered between ferroptosis and motor neuron death in ALS. Decreased levels of GPx4 have been found in the spinal cord and brain of ALS mouse models and in the post-mortem spinal cord of ALS patients [137]. Magnetic resonance imaging also found iron accumulation in the motor cortices of some ALS patients and in spinal cords of ALS animal models [138]. Low levels of GSH and high lipid peroxidation levels detected in the red blood cells of ALS patients confirm an alteration in oxidative state that is very similar to the ferroptosis mechanism [139]. From different studies found in the literature, several molecules have emerged that can intervene in the modulation of ferroptosis to reduce the progression of the disease. In a study conducted by Chen L. et al., on NSC-34 cells expressing the SOD mutant, Fer-1 was seen to be able to increase cell viability by inhibiting lactoperoxidase (LPO) activity and resulting in a reduction in lipid ROS; furthermore, in addition to Fer-1, it has been also observed that lipro-1 is able to inhibit LPO activity, resulting in increased cell viability [140]. On the contrary, studies conducted by Devos D. et al. on transgenic mice have found that deferiprone is a molecule able, through inhibition of LPO, to reduce iron accumulation in the spinal cord, increase the survival of study models, and reduce the markers used for oxidative phenomena [141]. Vitamin E also appears to be involved in inhibition of the ferroptotic pathway, promoting the attenuation of ALS. In fact, in a study by Chen L. et al. it was seen that the vitamin, in GPX4NIKO mouse models, not only delays the onset of paralysis but also manages to delay the death that is induced by GPX4 excision [142].

4.3. Cardiovascular Diseases

Scientific evidence has shown that altered iron homeostasis and ferroptosis are closely related to cardiovascular diseases as the accumulation of iron in the myocardium causes cardiotoxicity and triggers the alteration of normal cardiac function [143,144]. Additionally, Fang et al. showed that in the heart, doxorubicin (also known as Adriamycin, an anthracycline antibiotic with antineoplastic action that has a broad spectrum of antitumor activity) can trigger ferroptosis and free iron released from heme degradation can cause cardiac damage [145]. However, it is important to emphasize that even an iron deficiency can be harmful to cardiomyocytes as it can lead to an alteration in the contractile and metabolic activity of the cells themselves [146]. It is therefore stressed in hearts the importance of a regular and modulated iron homeostasis in which hepcidin is the main regulator. This protein, synthesized in the liver, can inhibit the activity of ferroportin, the only known iron exporter. Regulation of ferroportin is critical for iron homeostasis; the inhibition by hepcidin results in an iron decrease, while hepcidin depletion, which can be due to genetic mutations or blood transfusions, causing iron overload can trigger ferroptotic processes [147]. This state can be therapeutically partially restored by iron chelators or genetic regulation of ferroptosis by acting on specific targets such as SLC7A11 [148,149]. In this context, a promising strategy to counteract the accumulation of free iron may be represented by iron chelators, such as deferoxamine and deferiprone, which counteract the overload of circulating metal [145,150].

4.4. Ischemic Reperfusion Injury

Ischemia is an imbalance between the supply (perfusion) and the demand for oxygenated blood to a tissue or organ which leads to consequent functional, biochemical, and morphological alterations, followed by potential cellular necrosis of the affected area. The restoration of blood flow in an ischemic tissue can lead to an exacerbation of the damage, a condition known as “ischemic reperfusion injury” (IRI). IRI contributes to mortality and morbidity in many pathological conditions, including myocardial infarction and stroke, and occurs with a variety of surgical interventions where blood flow is temporarily blocked but then reperfused. The IRI process is multifactorial and not yet fully elucidated. In general, its pathogenesis involving different mechanisms can be divided into two different steps: the ischemic state and the reperfusion state. During ischemia, the interruption of the oxygen supply causes the blockage of mitochondrial oxidative phosphorylation and the consequent drastic reduction in ATP production, which becomes almost complete (about 90–95%) after about 40–60 min [151,152]. There is also an increase in anaerobic glycolysis that generates lactate and causes a change in intracellular pH that drops to a value of 6.2 after about ten minutes [153]. An ionic imbalance is therefore established also due to the blockage of the Na+/K+ and Na+/Ca2+ pumps; Na+ and Ca2+ accumulate inside the cell which, combined with the accumulation of other metabolites such as lactate and protons, draws water inside the cell, causing swelling [154,155]. Reperfusion provides oxygen and allows the replenishment of substrates in the ischemic area that are essential to produce ATP, glucose, and fatty acids, all of which are important for cell survival but can also contribute to exacerbating ischemic damage. In fact, during reperfusion, the enhancement of mitochondrial respiration leads to the generation of large amounts of ROS which, accompanied by upregulation of oxidative enzymes including xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidase (NOX), cyclooxygenase, lipoxygenase, and iNOS, cause a complex inflammatory response, leading to exacerbation of ischemic injury [156,157]. Recently, ferroptosis has been studied as a potential contributor to the events triggering ischemic injury [11]. In detail, during the reperfusion phase and not in the ischemic one, several key events of ferroptosis occur, including ROS exacerbation, increased intracellular iron and malondialdehyde concentrations, lipid peroxidation, reduced mitochondrial volume, and reduced or lost mitochondrial cristae [156]. Therefore, the synthesis or discovery of new molecules capable of antagonizing oxidative stress and the ferroptosis molecular targets may contribute to alleviating IRI and suppressing the inflammatory response. Chen et al., 2023, demonstrated that synthesized chitosan-derived nitrogen-doped carbon dots (CNDs), a synthetic product with ROS scavenging capabilities, protected the liver against IRI by suppressing oxidative stress damage [158]. As mentioned earlier, IRI can affect different organs of the body; in fact, we observe that in addition to the liver, the pathology can also affect the brain, kidneys, lungs, myocardium, etc., and obviously the inhibitory action of the different molecules towards the pathology and ferroptosis will be different. Wu J.R. et al. in their study showed how ischemic stroke results in the degeneration of the tau protein (protein involved in neuronal microtubule formation and iron export), causing iron accumulation and worsening of IRI symptoms. Scholars have also seen that there are molecules that can intervene in this condition, inhibiting the progression of the process; examples are liprostatin-1 and ferrostatin-1 [159]. At the cardiac level, on the other hand, myocardial reperfusion injury results in the death of cardiac myocytes, and it has also been seen in clinical studies that myocardial iron is a risk factor as it results in left ventricular remodeling after reperfusion [160]. Fang et al. in their study demonstrated how the intervention of ferrostatin-1, a synthetic inhibitor of ferroptosis that can both reduce lipid peroxidation and act as a scavenger, is of paramount importance in treating the condition; iron chelation can also result in improvements in acute and chronic IRI [145]. IRI can also affect the kidneys, in which case what is observed is an increase in reactive oxygen species, a direct involvement of iron, which as it accumulates triggers the ferroptotic process, resulting in renal tubular cell death [161]. However, it is important to emphasize that in renal IRI, one cannot exclusively target ferroptosis but one must also pay attention to necrosis. In a study conducted by Pefanis et al., it was seen that there is a direct correlation between the two pathways and therefore inhibition of only one pathway is not sufficient to result in improvement [162]. Thus, it follows from these studies how IRI might be related to ferroptosis and how the use of chelating agents and ferroptosis inhibitors may counteract the progression of the disease.

5. Ferroptosis Modulators

The association of ferroptosis with many diseases and the possibility of counteracting tumor growth and reducing drug resistance have contributed to a significant growth of interest in ferroptosis as potential therapeutic target (see Table 2 and Table 3). In this context, the continuous discovery of new drugs able to induce or inhibit ferroptosis is crucial to the research. There are many ways to induce ferroptosis, but the main systems involved in the process are iron homeostasis, the system Xc, and GPx4 catalytic action, and in some cases the action directed on one of these systems may trigger the blockage or activation of another also implicated in the process. Among the molecules that may modulate the death process, RAS-selective lethal 3 (RSL-3) is a compound that selectively inhibits the activity of GPx4, leading to downregulation of some factors involved in ferroptosis, such as Activating Transcription Factor 4 (ATF4) and SLC7A11 [87,163]. GPx4 inhibition leads to the imbalance of oxidative defenses and an increase in oxidative stress that consequently leads to ferroptosis; thus, inhibitors of GPx4 pathway can be exploited against highly aggressive forms of cancer such as glioblastoma, one of the most malignant brain tumors [164]. In addition, Erastin can also act directly on the system Xc through selective inhibition of this pathway, which will result in reduced cystine cellular uptake. The consequent reduced availability of cysteine will lead to the depletion of GSH, indirect inhibition of GPx4, and an increase in lipid peroxidation [2]. Overall, erastin has demonstrated multipotential properties that make it a selective candidate for cancer treatment as a chemotherapeutic drug to enhance the sensitivity of cancer cells [165,166]. Another synthetic inducer of ferroptosis is FIN56, which also acts by causing the permeabilization of the lysosomal membrane (LMP) [167]. FIN56 derives from a class of molecules called “caspase-3/7-independent lethals” (CILs) that have been shown to induce cell death through ferroptosis and necrotic death [168]. Within this category, CIL56, named FIN56, is the compound that has shown the greatest activity in inducing ferroptosis at low concentrations. FIN56 acts by promoting GPx4 protein degradation and thereby causing ferroptosis [169]. Some experiments on tumor cell lines have shown that after treatment with FIN56, although the amount of GPx4 decreases, its transcriptional levels increase, demonstrating that FIN56 does not act at the transcriptional level but in the post-translational phase, causing a depletion of GPx4 [170]. Furthermore, FIN56 activates squalene synthase, an enzyme directly involved in the production of cholesterol, and this leads to the blockade of some natural antioxidant systems such as coenzyme Q10 (CoQ10) and Selenocysteine-tRNA (Sec-tRNA) [87,169]. Besides FIN56, other inhibitors of GPX4 are Bufotaline (BT) and palladium–pyrithione complex (PdPT). In a study conducted by Zhang W. et al., it was seen that BT can trigger the ferroptotic process by inhibiting GPX4. The investigators used the A549 cell line (lung cancer cells) and saw that the compound inhibited cell proliferation by inducing ferroptosis. Through different techniques, such as immunoblotting and the immunoprecipitation assay, it was seen that bufotaline inhibited not only the protein expression of GPX4 but also induced its degradation; in addition, this molecule was also associated with the ability to increase intracellular Fe2+ concentration and induce lipid peroxidation [171]. PdPT activity, on the other hand, was observed by Li Y. et al. in a study conducted on NSCLC A549 and NCI-H1299, two cancer cell lines. The investigators saw that the palladium–pyrithione complex has the ability to inhibit deubiquitinases (DUBs), enzymes critical for cell metabolism and survival; furthermore, inhibition of DUB resulted in the activation of caspases, triggering the apoptotic pathway, and degradation of GPX4, triggering ferroptosis, suggesting the involvement of the complex in the ferroptotic process [172]. Ferroptosis regulators can be divided based on the molecular mechanism by which they act. In this context, Deferoxamine is a chelating agent used for iron and aluminum toxicity that binds to free iron in the body, making it available for elimination through urine and feces. By reducing the availability of free iron within cells, deferoxamine prevents ROS production and lipid peroxidation [2]. Deferoxamine has been demonstrated to inhibit ferroptosis, promoting recovery of traumatic spinal cord injury and protecting liver cells from induced cell death in a model of acute liver necrosis [6,173]. Another well-known iron chelator is Deferiprone (DFP, Ferriprox), orally administered and approved by the FDA for the treatment of patients with iron overload. DFP, as deferoxamine, reducing free iron levels may be considered a promising therapeutic drug which prevents oxidative stress, resulting in a decreased inflammation state [174,175]. Between the ferroptosis inhibitors, Ferrostatin-1 is a synthetic antioxidant able to generate a complex with iron, preventing oxidative stress from the Fenton reaction [96]. Specifically, ferrostatin-1 may act as a scavenger; binding with hydroperoxyl radicals, it breaks the peroxyl chain mechanism produced by ferrous iron [133,176]. Similarly, to ferrostatin-1, Liproxstatin-1 (Lipro-1) can block ferroptosis, even in the presence of known ferroptosis inducers such as FIN56 or RSL-3 [75,177]. Fan et al. in a study on an oligodendrocyte (OLN-93 cell line) model of ferroptosis induced by RSL-3 demonstrated that concentrations between 115.3 nM and 1 μM of Lipro-1 reduced lipid peroxidation, improved GPx4 expression, and increased GSH levels [178]. The ferroptosis modulators described above are semisynthetic derivatives (for a broader overview refer to Table 2 and Table 3), but growing evidence highlights natural products as a potent drug-discovery resource and some of them such as polyphenols can induce or inhibit programmed cellular death [179,180,181].

6. Natural Ferroptosis Regulators

Natural compounds are not only safer, as they are less toxic, but they act more specifically on the targets involved in ferroptosis and are also more accessible and economical [182]. These compounds can act directly on target cells by inducing oxidative stress or can affect cellular transport and metabolism of iron and its homeostasis or cause GSH depletion, leading to the formation of free radicals and damage to cell membranes, which are typical events of ferroptosis (see Table 2 and Table 3).

6.1. Natural Inducers

Among natural inducers, Artemisinin, a naturally occurring compound extracted from Artemisia annua, is a sesquiterpene consisting of three isoprene units linked together and presenting a peroxide bridge within the structure [183]. Typically, artemisinin and its derivatives are used as antimalarial drugs and are being studied for their potential use in the treatment of other diseases, including cancer [184]. In addition to the strong antimalarial activity, artemisinin, thanks to its chemical structure and the peroxide bridge, may affect iron metabolism and the Xc/GPx4 axis, causing an increase in ROS generation, which is the basis of ferroptosis [185]. Among the artemisinin derivatives, we can also consider artesunate and artemether, both ferroptosis inducers. In the first case, artesunate promotes the hydrolysis of ferritin, increasing the amount of free iron ions and contributing to the imbalance of intracellular iron metabolism. The intracellular increase in free iron through the Fenton reaction improves ROS generation, lipid peroxidation, and promotes ferroptosis in pancreatic ductal adenocarcinoma. The second derivate, artemether, acts on several ferroptosis targets, including increased iron levels and lipid peroxidation products, decreased GSH, and the p53 pathway. Specifically, p53 is crucial for artemether-induced ferroptosis because artemether not only promotes the expression but also the nuclear import of p53, which, in turn, reduces the expression or causes a decreased activity of the system Xc in cells [186]. Among other natural inducers, we can also consider isothiocyanates (ITCs), a class of sulfur-containing organic compounds derived from thiocyanic acid and containing the functional group -N=C=S. These compounds, present in some plants of the Brassicaceae family, such as broccoli, cabbage, cauliflower, and radishes, are known to have antitumor, antimicrobial, and anti-inflammatory properties [187]. Among all, the one that exhibits the highest antitumor activity is phenethyl isothiocyanate (PEITC). In fact, it has been shown that this compound is able to block the growth and survival of some tumor cell lines. Moreover, through a mechanism that is not yet fully defined, it induces ROS production and ferroptosis in several cellular lines [188]. Kasukabe T. et al. demonstrated that in pancreatic cancer, the combined treatment of PEITC with Cotylenin A (CN-A), a natural antitumor drug, has a synergistic antiproliferative activity by inhibition of the growth of MIAPaCa-2, PANC-1, and gemcitabine-resistant PANC-1 cells [189]. Another compound with already known apoptotic and antitumor activity is Gambogic acid (GA). This compound, mainly extracted from G. hanburyi and G. morella, well-known plants in Chinese culture, not only blocks cell proliferation but scientific evidence shows it also inhibits invasion, metastasing processes, and angiogenesis in various tumor cell lines [190,191,192,193]. GA induces apoptosis and autophagy through multiple mechanisms and perturbs the cellular redox balance, inducing ROS generation and ferroptosis death in tumor cells [194].

6.2. Natural Inhibitors

Through screening of natural compound libraries, it has emerged that Glycyrrhizin (GLY) is able to block ferroptosis. GLY is an organic compound found in the root of liquorice (Glycyrrhiza glabra) that gives the plant its sweet taste. It is a mixture of triterpenoid saponins and has been the subject of numerous studies for its pharmacological properties, including anti-inflammatory, antioxidant, immunomodulatory, and antiviral properties [187,195]. Wang et al. have shown that GLY reduces ferroptosis in hepatocytes during acute liver failure (ALF) by activating various pathways, such as Nrf2/HO-1/HMGB1, to counteract oxidative stress involved in ferroptosis [196]. There are some ferroptosis modulators that do not act directly on iron metabolism or on the main mechanisms underlying this type of cell death but act indirectly on other pathways that, in parallel, can affect the ferroptosis process. In this context, several pathological conditions involving the inflammatory process may be worsened by the activation of the JAK-STAT pathway, which indirectly leads to ferroptosis. Indeed, the binding of cytokines such as TNF and IL-6 to their receptors causes the dimerization and phosphorylation of JAK, which in turn activates the STATs; particularly, STAT3 acts at the nuclear level increasing the expression of hepcidin, which inhibits iron export, while STAT1 activation inhibits the system Xc, with both conditions resulting in ferroptosis [197]. Gao et al. studied the indirect correlation between the JAK-STAT pathway, ferroptosis, and tumor progression in certain cell lines. Ferroptosis was induced by incubating PDAC cell lines with erastin, and then Cryptotanshinone, an inhibitor of the process, was added. Cryptotanshinone is a natural chemical compound belonging to the tanshinone class, isolated from the root of Salvia miltiorrhiza; the study demonstrated that Cryptotanshinone can block erastin-induced ferroptosis by antagonizing STAT3 [198]. In addition, N-acetylcysteine (NAC), a chemical agent with a thiol group derived from L-cysteine, acting as an antioxidant agent alleviates ferroptosis and reduces cell death [199]. NAC not only blocks the production of some inflammatory cytokines such as TNF-α and IL-1β, also blocking the JAK-STAT pathway, but it inhibits the production of leukotrienes, inflammatory mediators implicated in various pathologies including asthma, allergies, and intracerebral hemorrhage. NAC prevents cell death by targeting nuclear ALOX5-derived reactive lipid species, which are normally precursors of ferroptosis. This action leads to a lower demand for glutathione to restore iron and lipid homeostasis, thus enabling an increase in cellular GSH levels. Moreover, NAC can act as a donor of sulfhydryl groups, further increasing GSH synthesis. An increase in GSH can help protect cells from death by ferroptosis since glutathione is an important endogenous antioxidant that can neutralize free radicals and ROS, thereby reducing oxidative stress and protecting cellular membranes from damage [200].


A growing body of studies highlights polyphenol’s multiple effects against ferroptosis and correlates the intake of foods rich in these compounds including fruits, vegetables, and cereals to the decreased incidence of chronic and tumor diseases [201]. Generally, polyphenols due to their antioxidant and anti-inflammatory effects may act as ferroptosis inhibitors by counteracting and mitigating the underlying mechanisms of oxidative stress, although it is known that polyphenols’ activity depends on the dose, treatment duration, and cell/tissue specificity; so, it is more correct to classify them as inducers or inhibitors or both. Among polyphenols, many flavonoids have been reported to be potential ferroptosis inhibitors. In detail, flavonoids belong to the group of polyphenols and based on their chemical structure can be divided in flavones, flavonols, flavanones, anthocyanidins, isoflavones, and flavanols [202]. Curcumin, a yellow polyphenolic pigment, particularly present in the tuberized rhizome (root) of various species of turmeric, such as Curcuma longa (or Curcuma domestica), is a powerful antioxidant with beneficial properties in the treatment of oxidative stress [203]. Treatment with curcumin significantly increases nuclear transfer of Nrf2 and the expression of Gpx4 and HO-1 and inhibits glucose-induced ferroptosis in cardiomyocytes [204]. Guerrero-Hue et al. demonstrated, on mouse models with acute kidney injury, that curcumin reduces lipid peroxidation, inflammation, and renal damage associated with rhabdomyolysis by decreasing ferroptosis-mediated cell death [205]. In addition, Kose et al. observed a protective effect of curcumin treatment (20 μM for 24 h) against erastin-induced ferroptosis in mouse insulinoma pancreatic cells (MIN6). In detail, the study investigated the effects of two polyphenols, curcumin and epigallocatechin-3-gallate (EGCG), against iron loading and ferroptosis; both compounds intervene positively by acting as iron chelators and preventing GSH depletion, GPx4 inactivation, and lipid peroxidation [206]. The iron chelating activity of EGCG could be related to the molecule’s ability to modulate the expression of IRP involved in iron homeostasis. These proteins, activated under iron-deficient conditions, inhibit ferritin activity and simultaneously stabilize TfR1 mRNA. The potentiality of EGCG as a ferroptosis inhibitor is confirmed by Yang et al., who demonstrated that its administration attenuates iron metabolism disorders, increases Nrf2 and GPx4 expression, and elevates antioxidant capacity in iron overload mice [207]. An increase in antioxidant activity has been shown also by apigenin, a known flavone found in chamomile leaves and celery; it was able to block oxidative stress and confer neuroprotection against kainic acid-induced ferroptosis by inducing GPx4 and SIRT1. Shao C. et al. on human neuroblastoma SH-SY5Y cells showed that apigenin protects against ferroptosis induced by myeloperoxidase overexpression and kainic acid [208]. Another well-known flavonoid that has been correlated with ferroptosis is quercetin, a flavonol particularly found in grapes, red onions, blueberries, apples, and radicchio [209]. As other polyphenols, quercetin possesses a high antioxidant activity which gives the compound a protective action against ferroptosis. Li X. et al., after over-loading mice with a ferric–dextran complex, demonstrated that quercetin administration attenuated lipid peroxidation in hepatic, renal, and cardiac cells thanks to its iron chelating nature [210]. Furthermore, Li et al. showed that quercetin (0.03 µM), and its metabolite quercetin Diels-Alder anti-dimer, can protect bone marrow-derived mesenchymal stem cells from erastin-induced ferroptosis, possibly through the antioxidant pathway [211]. Another polyphenol involved in countering the ferroptosis process is baicalein. In a study conducted by Xie Y. et al., it was observed that baicalein exhibits protective activity in human pancreatic cancer cells (BxPc3) and epithelioid carcinoma cells (PANC1) of the pancreas. The molecule inhibits GSH depletion, GPx4 degradation, and lipid peroxidation. Furthermore, the study demonstrated that baicalein inhibits Nrf2 degradation and reduces oxidative stress in PCNA1 cells [212].

7. Conclusions

In recent years, an emerging enthusiasm in ferroptosis processes and the role it plays in the onset and progression of various diseases has driven numerous studies. An in-depth understanding of all the molecular mechanisms involved in this form of cell death could facilitate the identification of molecular targets more suitable for the treatment of different diseases and optimize clinical prevention, diagnostics, and clinical treatment. To date, many mechanisms of ferroptosis have not yet been fully elucidated, including the trigger of the process, which may be caused by iron accumulation, GPx4 and system Xc inhibition, ROS increase, and lipid peroxidation. It has not yet been fully clarified whether the alteration of a single factor is sufficient to trigger ferroptosis or whether the beginning of the process depends on a synergy between all these factors. In addition, ferroptosis shows some regulatory signals common to other types of cell death and this makes difficult a net distinction between the different mechanisms of death. As discussed, many synthetic and natural-origin molecules have been tested for the regulation of ferroptosis and for the treatment of possibly related pathologies, including neurodegenerative, cardiovascular, or metabolic disorders and many cancer types. It is known that the activation of ferroptosis in some types of cancer can induce the death not only of ordinary cancer cells but also of those resistant to pharmacologic treatment. This research unequivocally highlights the importance of natural compounds as potential modulators and inducers of ferroptosis, emphasizing their revolutionary prospects in the treatment of various pathologies. Delving into the interactions between these natural compounds and the regulatory mechanisms of ferroptosis paves the way for targeted therapeutic strategies, and understanding such processes can not only contribute to elucidating some different mechanisms but also guide the development of more effective and specific therapies. Indeed, plants produce a large multitude of antioxidant compounds, all potentially usable to fight the ferroptosis process and, with it, slow down or block the progression of the related disease. However, despite growing evidence pointing to natural products as ideal compounds for both single- and multi-drug treatment against ferroptosis, studies are still needed to elucidate their pharmacokinetics, bioavailability, nuclear pharmacology, and to optimize dosage for potential clinical therapy. Furthermore, this research not only enhances our understanding of the links between ferroptosis and pathologies but also opens the door to new innovative therapeutic perspectives, promoting an integrated approach to disease management through the responsible and targeted use of natural modulators of ferroptosis. Therefore, future studies should aim to clarify specific molecular targets to avoid side effects and develop drugs with highly specific molecular targets.

Author Contributions

E.T., S.P. and G.T.P. performed the literature review and drafted the paper; S.P., D.B., A.C., C.M., S.F. and G.L., assisted in the literature review; E.T., G.T.P. and S.P. critically revised the paper. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


Reactive oxygen species (ROS); Glutathione (GSH); Glutathione peroxidase 4 (GPx4); Tumor necrosis factor alpha (TNFα); Interleukin-1,6 (IL-1β, IL-6); Rat sarcoma (RAS); Transferrin receptor 1 (TfR1); Hydrogen peroxide (H2O2); Hydroxyl radical (OH); Deoxyribonucleic acid (DNA); Adenosine triphosphate (ATP); Divalent metal transporter 1 (DMT1); Transferrin (Tf); Transferrin receptor (TfR); Iron regulatory proteins-1,2 (IRP1,2); Nuclear receptor coactivator 4 (NCOA4); E3 ubiquitin ligase (HERC2); Coatomer subunit zeta-1 (COPZ1); Polyunsaturated fatty acids (PUFAs); Long-chain fatty-acid-CoA ligase 4 (ACSL4); Lipoxygenases (LOXs); Lipid peroxides (LOOH); Disulfide form (GSSH); Erythroid nuclear factor 2-related factor (Nrf2); Kelchlike ECH-associated protein 1 (Keap1); Antioxidant response elements (ARE); Diamine acetyltransferase 1 (SAT1); Mitochondrial glutaminase (GLS2); Dipeptidyl peptidase 4 (DPP4); Cyclin-dependent kinase inhibitor 1A (CDKN1A); Alzheimer’s disease (AD); Parkinson’s disease (PD); Huntington’s disease (HD); Amyotrophic lateral sclerosis (ALS); Tert-butyl hydroperoxide (t-BHP); Arachidonate 5-lipoxygenase (ALOX5); Superoxide dismutase 1 (SOD1); Cardiovascular disease (CVD); Ferroptosis-suppressor protein 1 (FSP1); RAS-selective lethal 3 (RSL-3); Lysosomal membrane (LMP); Caspase-3/7-independent lethals (CILs); Coenzyme Q10 (CoQ10); Deferiprone (DFP, Ferriprox); Liproxstatin-1 (Lipro-1); Isothiocyanates (ITCs); Phenethyl isothiocyanate (PEITC); Cotylenin A (CN-A); Gambogic Acid (GA); Glycyrrhizin (GLY); Acute liver failure (ALF); Heme oxygenase (HO-1); High-mobility group box 1 (HMGB1); N-acetylcysteine (NAC); Kainic Acid (KA), Interferon gamma (IFN-γ); Solute Carrier Family 7 Member-11,2 (SLC7A11,2); dihydroorotate dehydrogenase (DHODH); GTP cicloidrolasi I (GCH1); Tetraidrobiopterina (BH4); flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2); nicotinamide–adenine dinucleotide phosphate (NADP); dihydroorotate (DHO); orotate (OA); mouse double minute 2 (MDM2); Huntingtin (Htt); Activating Transcription Factor 4 (ATF4); Voltage-Dependent Anion Channel 2 (VDAC2); N2,N7-dicicloesil-9-(idrossiimmino)-9H-fluorene-2,7-disolfonammide (FIN56); Selenocysteine-tRNA (Sec-tRNA); High-Mobility Group Box 1 (HMGB1); signal transducer and activator of transcription (STAT); Janus chinasi (JAK); epigallocatechin-3-gallate (EGCG).


  1. D’Arcy, M.S. Cell death: A review of the major forms of apoptosis, necrosis and autophagy. Cell Biol. Int. 2019, 43, 582–592. [Google Scholar] [CrossRef] [PubMed]
  2. 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]
  3. Capelletti, M.M.; Manceau, H.; Puy, H.; Peoc’h, K. Ferroptosis in Liver Diseases: An Overview. Int. J. Mol. Sci. 2020, 21, 4908. [Google Scholar] [CrossRef] [PubMed]
  4. 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. [Google Scholar] [CrossRef] [PubMed]
  5. 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]
  6. Xie, Y.; Hou, W.; Song, X.; Yu, Y.; Huang, J.; Sun, X.; Kang, R.; Tang, D. Ferroptosis: Process and function. Cell Death Differ. 2016, 23, 369–379. [Google Scholar] [CrossRef] [PubMed]
  7. Stockwell, B.R.; Angeli, J.P.F.; Bayir, H.; Bush, A.I.; Conrad, M.; Dixon, S.J.; Fulda, S.; Gascón, S.; Hatzios, S.K.; Kagan, V.E.; et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 2017, 171, 273–285. [Google Scholar] [CrossRef]
  8. Greenough, M.A.; Lane, D.J.R.; Balez, R.; Anastacio, H.T.D.; Zeng, Z.; Ganio, K.; McDevitt, C.A.; Acevedo, K.; Belaidi, A.A.; Koistinaho, J.; et al. Selective ferroptosis vul-nerability due to familial Alzheimer’s disease presenilin mutations. Cell Death Differ. 2022, 29, 2123–2136. [Google Scholar] [CrossRef]
  9. Wang, K.; Chen, X.-Z.; Wang, Y.-H.; Cheng, X.-L.; Zhao, Y.; Zhou, L.-Y.; Wang, K. Emerging roles of ferroptosis in cardiovascular diseases. Cell Death Discov. 2022, 8, 394. [Google Scholar] [CrossRef]
  10. Xie, L.; Fang, B.; Zhang, C. The role of ferroptosis in metabolic diseases. Biochim. Biophys. Acta—Mol. Cell Res. 2023, 1870, 119480. [Google Scholar] [CrossRef]
  11. Yan, H.F.; Tuo, Q.Z.; Yin, Q.Z.; Lei, P. The pathological role of ferroptosis in ische-mia/reperfusion-related injury. Zool. Res. 2020, 41, 220–230. [Google Scholar] [CrossRef] [PubMed]
  12. Zhang, X.; Du, L.; Qiao, Y.; Zhang, X.; Zheng, W.; Wu, Q.; Chen, Y.; Zhu, G.; Liu, Y.; Bian, Z.; et al. Ferroptosis is governed by differential regulation of transcription in liver cancer. Redox Biol. 2019, 24, 101211. [Google Scholar] [CrossRef] [PubMed]
  13. Liao, D.; Yang, G.; Yang, Y.; Tang, X.; Huang, H.; Shao, J.; Pan, Q. Identification of Pannexin 2 as a Novel Marker Correlating with Ferroptosis and Malignant Phenotypes of Prostate Cancer Cells. OncoTargets Ther. 2020, 13, 4411–4421. [Google Scholar] [CrossRef] [PubMed]
  14. Badgley, M.A.; Kremer, D.M.; Maurer, H.C.; DelGiorno, K.E.; Lee, H.-J.; Purohit, V.; Sagalovskiy, I.R.; Ma, A.; Kapilian, J.; Firl, C.E.M.; et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 2020, 368, 85–89. [Google Scholar] [CrossRef] [PubMed]
  15. Yu, M.; Gai, C.; Li, Z.; Ding, D.; Zheng, J.; Zhang, W.; Lv, S.; Li, W. Targeted exosome-encapsulated erastin induced ferroptosis in triple negative breast cancer cells. Cancer Sci. 2019, 110, 3173–3182. [Google Scholar] [CrossRef] [PubMed]
  16. Zeng, C.; Tang, H.; Chen, H.; Li, M.; Xiong, D. Ferroptosis: A new approach for immunotherapy. Cell Death Discov. 2020, 6, 122. [Google Scholar] [CrossRef] [PubMed]
  17. Roh, J.-L.; Kim, E.H.; Jang, H.J.; Park, J.Y.; Shin, D. Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. Cancer Lett. 2016, 381, 96–103. [Google Scholar] [CrossRef]
  18. Chen, X.; Kang, R.; Kroemer, G.; Tang, D. Broadening horizons: The role of ferroptosis in cancer. Nat. Rev. Clin. Oncol. 2021, 18, 280–296. [Google Scholar] [CrossRef]
  19. Aizawa, S.; Brar, G.; Tsukamoto, H. Cell Death and Liver Disease. Gut Liver 2020, 14, 20–29. [Google Scholar] [CrossRef]
  20. Xu, T.; Ding, W.; Ji, X.; Ao, X.; Liu, Y.; Yu, W.; Wang, J. Molecular mechanisms of ferroptosis and its role in cancer therapy. J. Cell. Mol. Med. 2019, 23, 4900–4912. [Google Scholar] [CrossRef]
  21. Thomas, C.; Mackey, M.M.; Diaz, A.A.; Cox, D.P. Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: Implications for diseases associated with iron accumulation. Redox Rep. 2009, 14, 102–108. [Google Scholar] [CrossRef] [PubMed]
  22. Nadadur, S.S.; Srirama, K.; Mudipalli, A. Iron transport & homeostasis mechanisms: Their role in health & disease. Indian J. Med. Res. 2008, 128, 533–544. [Google Scholar]
  23. Abbaspour, N.; Hurrell, R.; Kelishadi, R. Review on iron and its importance for human health. J. Res. Med. Sci. 2014, 19, 164–174. [Google Scholar]
  24. Fenton, H.J.H. LXXIII.—Oxidation of tartaric acid in presence of iron. J. Chem. Soc. Trans. 1894, 65, 899–910. [Google Scholar] [CrossRef]
  25. Lieu, P.T.; Heiskala, M.; Peterson, P.A.; Yang, Y. The roles of iron in health and disease. Mol. Asp. Med. 2001, 22, 1–87. [Google Scholar] [CrossRef] [PubMed]
  26. Wallace, D.F. The Regulation of Iron Absorption and Homeostasis. Clin. Biochem. Rev. 2016, 37, 51–62. [Google Scholar] [PubMed]
  27. Chen, X.; Yu, C.; Kang, R.; Tang, D. Iron Metabolism in Ferroptosis. Front. Cell Dev. Biol. 2020, 8, 590226. [Google Scholar] [CrossRef]
  28. Ajoolabady, A.; Aslkhodapasandhokmabad, H.; Libby, P.; Tuomilehto, J.; Lip, G.Y.; Penninger, J.M.; Richardson, D.R.; Tang, D.; Zhou, H.; Wang, S.; et al. Ferritinophagy and ferroptosis in the management of metabolic diseases. Trends Endocrinol. Metab. 2021, 32, 444–462. [Google Scholar] [CrossRef]
  29. Sun, K.; Li, C.; Liao, S.; Yao, X.; Ouyang, Y.; Liu, Y.; Wang, Z.; Li, Z.; Yao, F. Ferritinophagy, a form of autophagic ferroptosis: New insights into cancer treatment. Front. Pharmacol. 2022, 13, 1043344. [Google Scholar] [CrossRef]
  30. Mancias, J.D.; Pontano Vaites, L.; Nissim, S.; Biancur, D.E.; Kim, A.J.; Wang, X. Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. eLife 2015, 4, 10308. [Google Scholar] [CrossRef]
  31. Ryu, M.-S.; Duck, K.A.; Philpott, C.C. Ferritin iron regulators, PCBP1 and NCOA4, respond to cellular iron status in developing red cells. Blood Cells Mol. Dis. 2018, 69, 75–81. [Google Scholar] [CrossRef] [PubMed]
  32. Zhang, Y.; Kong, Y.; Ma, Y.; Ni, S.; Wikerholmen, T.; Xi, K.; Zhao, F.; Zhao, Z.; Wang, J.; Huang, B.; et al. Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines. Oncogene 2021, 40, 1425–1439. [Google Scholar] [CrossRef]
  33. Hou, W.; Xie, Y.; Song, X.; Sun, X.; Lotze, M.T.; Zeh, H.J., 3rd; Kang, R.; Tang, D. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 2016, 12, 1425–1428. [Google Scholar] [CrossRef] [PubMed]
  34. Golej, D.L.; Askari, B.; Kramer, F.; Barnhart, S.; Vivekanandan-Giri, A.; Pennathur, S.; Bornfeldt, K.E. Long-chain acyl-CoA synthetase 4 modulates prostaglandin E₂ release from human arterial smooth muscle cells. J. Lipid Res. 2011, 52, 782–793. [Google Scholar] [CrossRef] [PubMed]
  35. 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]
  36. 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. [Google Scholar] [CrossRef] [PubMed]
  37. Li, C.; Zhang, Y.; Liu, J.; Kang, R.; Klionsky, D.J.; Tang, D. Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death. Autophagy 2021, 17, 948–960. [Google Scholar] [CrossRef]
  38. Bridges, R.J.; Natale, N.R.; Patel, S.A. System xc⁻ cystine/glutamate antiporter: An update on molecular pharmacology and roles within the CNS. Br. J. Pharmacol. 2012, 165, 20–34. [Google Scholar] [CrossRef]
  39. Bannai, S. Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J. Biol. Chem. 1986, 261, 2256–2263. [Google Scholar] [CrossRef]
  40. Lin, C.H.; Lin, P.P.; Lin, C.Y.; Lin, C.H.; Huang, C.H.; Huang, Y.J.; Lane, H.Y. Decreased mRNA expression for the two subunits of system xc(−), SLC3A2 and SLC7A11, in WBC in patients with schizophrenia: Evidence in support of the hypo-glutamatergic hypothesis of schizophrenia. J. Psychiatr. Res. 2016, 72, 58–63. [Google Scholar] [CrossRef]
  41. Doll, S.; Conrad, M. Iron and ferroptosis: A still ill-defined liaison. IUBMB Life 2017, 69, 423–434. [Google Scholar] [CrossRef] [PubMed]
  42. Liang, C.; Zhang, X.; Yang, M.; Dong, X. Recent Progress in Ferroptosis Inducers for Cancer Therapy. Adv. Mater. 2019, 31, e1904197. [Google Scholar] [CrossRef] [PubMed]
  43. Mariotti, M.; Ridge, P.G.; Zhang, Y.; Lobanov, A.V.; Pringle, T.H.; Guigo, R.; Hatfield, D.L.; Gladyshev, V.N. Composition and evolution of the vertebrate and mammalian selenoproteomes. PLoS ONE 2012, 7, e33066. [Google Scholar] [CrossRef] [PubMed]
  44. Flohé, L.; Toppo, S.; Orian, L. The glutathione peroxidase family: Discoveries and mechanism. Free Radic. Biol. Med. 2022, 187, 113–122. [Google Scholar] [CrossRef] [PubMed]
  45. Liu, H.; Forouhar, F.; Seibt, T.; Saneto, R.; Wigby, K.; Friedman, J.; Xia, X.; Shchepinov, M.S.; Ramesh, S.K.; Conrad, M.; et al. Characterization of a patient-derived variant of GPX4 for precision therapy. Nat. Chem. Biol. 2022, 18, 91–100. [Google Scholar] [CrossRef] [PubMed]
  46. Ursini, F.; Maiorino, M.; Hochstein, P.; Ernster, L. Microsomal lipid peroxidation: Mechanisms of initiation: The role of iron and iron chelators. Free Radic. Biol. Med. 1989, 6, 31–36. [Google Scholar] [CrossRef] [PubMed]
  47. Li, C.; Deng, X.; Xie, X.; Liu, Y.; Friedmann Angeli, J.P.; Lai, L. Activation of Glutathione Peroxidase 4 as a Novel Anti-inflammatory Strategy. Front. Pharmacol. 2018, 9, 1120. [Google Scholar] [CrossRef]
  48. Seibt, T.M.; Proneth, B.; Conrad, M. Role of GPX4 in ferroptosis and its pharmacological implication. Free Radic. Biol. Med. 2019, 133, 144–152. [Google Scholar] [CrossRef]
  49. Stipanuk, M.H. Metabolism of sulfur-containing amino acids: How the body copes with excess methionine, cysteine, and sulfide. J. Nutr. 2020, 150, 2494S–2505S. [Google Scholar] [CrossRef]
  50. Wei, X.; Yi, X.; Zhu, X.-H.; Jiang, D.-S. Posttranslational Modifications in Ferroptosis. Oxidative Med. Cell. Longev. 2020, 2020, 8832043. [Google Scholar] [CrossRef]
  51. Frei, B.; Kim, M.C.; Ames, B.N. Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc. Natl Acad. Sci. USA 1990, 87, 4879–4883. [Google Scholar] [CrossRef] [PubMed]
  52. Doll, S.; Freitas, F.P.; Shah, R.; Aldrovandi, M.; da Silva, M.C.; Ingold, I.; Grocin, A.G.; da Silva, T.N.X.; Panzilius, E.; Scheel, C.H.; et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 2019, 575, 693–698. [Google Scholar] [CrossRef] [PubMed]
  53. Vyas, V.K.; Ghate, M. CoMFA and CoMSIA studies on aryl carboxylic acid amide derivatives as dihydroorotate dehydrogenase (DHODH) inhibitors. Curr. Comput. Aided-Drug Des. 2012, 8, 271–282. [Google Scholar] [CrossRef] [PubMed]
  54. Fairus, A.M.; Choudhary, B.; Hosahalli, S.; Kavitha, N.; Shatrah, O. Dihydroorotate dehydrogenase (DHODH) inhibitors affect ATP depletion, endogenous ROS and mediate S-phase arrest in breast cancer cells. Biochimie 2017, 135, 154–163. [Google Scholar] [CrossRef] [PubMed]
  55. Fang, J.; Uchiumi, T.; Yagi, M.; Matsumoto, S.; Amamoto, R.; Takazaki, S.; Yamaza, H.; Nonaka, K.; Kang, D. Dihydro-orotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction. Biosci. Rep. 2013, 33, e00021. [Google Scholar] [CrossRef] [PubMed]
  56. 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]
  57. Kraft, V.A.N.; Bezjian, C.T.; Pfeiffer, S.; Ringelstetter, L.; Muller, C.; Zandkarimi, F.; Merl-Pham, J.; Bao, X.W.; Anastasov, N.; Kossl, J.; et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent. Sci. 2020, 6, 41–53. [Google Scholar] [CrossRef] [PubMed]
  58. Cronin, S.J.F.; Seehus, C.; Weidinger, A.; Talbot, S.; Reissig, S.; Seifert, M.; Pierson, Y.; McNeill, E.; Longhi, M.S.; Turnes, B.L.; et al. The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature 2018, 563, 564–568. [Google Scholar] [CrossRef]
  59. Fanet, H.; Capuron, L.; Castanon, N.; Calon, F.; Vancassel, S. Tetra-hydrobioterin (BH4) Pathway: From Metabolism to Neuropsychiatry. Curr. Neuropharmacol. 2021, 19, 591–609. [Google Scholar]
  60. Werner, E.R.; Blau, N.; Thöny, B. Tetrahydrobiopterin: Biochemistry and pathophysiology. Biochem. J. 2011, 438, 397–414. [Google Scholar] [CrossRef]
  61. 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]
  62. Lv, Y.; Wu, M.; Wang, Z.; Wang, J. Ferroptosis: From regulation of lipid peroxidation to the treatment of diseases. Cell Biol. Toxicol. 2022, 39, 827–851. [Google Scholar] [CrossRef] [PubMed]
  63. 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]
  64. Dodson, M.; de la Vega, M.R.; Cholanians, A.B.; Schmidlin, C.J.; Chapman, E.; Zhang, D.D. Modulating NRF2 in Disease: Timing Is Everything. Annu. Rev. Pharmacol. Toxicol. 2019, 59, 555–575. [Google Scholar] [CrossRef] [PubMed]
  65. Dinkova-Kostova, A.T.; Abramov, A.Y. The emerging role of Nrf2 in mitochondrial function. Free Radic. Biol. Med. 2015, 88 Pt B, 179–188. [Google Scholar] [CrossRef]
  66. Merry, T.L.; Ristow, M. Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) mediates exercise-induced mitochondrial biogenesis and the antioxidant response in mice. J. Physiol. 2016, 594, 5195–5207. [Google Scholar] [CrossRef] [PubMed]
  67. Silva, M.M.; Rocha, C.R.R.; Kinker, G.S.; Pelegrini, A.L.; Menck, C.F.M. The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells. Sci. Rep. 2019, 9, 17639. [Google Scholar] [CrossRef] [PubMed]
  68. Song, X.; Long, D. Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases. Front. Neurosci. 2020, 14, 267. [Google Scholar] [CrossRef] [PubMed]
  69. Kubbutat, M.H.; Vousden, K.H. Keeping an old friend under control: Regulation of p53 stability. Mol. Med. Today 1998, 4, 250–256. [Google Scholar] [CrossRef]
  70. Bates, S.; Vousden, K.H. p53 in signaling checkpoint arrest or apoptosis. Curr. Opin. Genet. Dev. 1996, 6, 12–18. [Google Scholar] [CrossRef]
  71. Ashcroft, M.; Taya, Y.; Vousden, K.H. Stress signals utilize multiple pathways to stabilize p53. Mol. Cell. Biol. 2000, 20, 3224–3233. [Google Scholar] [CrossRef] [PubMed]
  72. Honda, R.; Tanaka, H.; Yasuda, H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997, 420, 25–27. [Google Scholar] [CrossRef] [PubMed]
  73. Tao, W.; Levine, A.J. Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. Proc. Natl. Acad. Sci. USA 1999, 96, 3077–3080. [Google Scholar] [CrossRef] [PubMed]
  74. 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]
  75. 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] [PubMed]
  76. Zhang, W.; Gai, C.; Ding, D.; Wang, F.; Li, W. Targeted p53 on Small-Molecules-Induced Ferroptosis in Cancers. Front. Oncol. 2018, 8, 507. [Google Scholar] [CrossRef] [PubMed]
  77. Hu, W.; Zhang, C.; Wu, R.; Sun, Y.; Levine, A.; Feng, Z. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc. Natl. Acad. Sci. USA 2010, 107, 7455–7460. [Google Scholar] [CrossRef] [PubMed]
  78. 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]
  79. Kang, R.; Kroemer, G.; Tang, D. The tumor suppressor protein p53 and the ferroptosis network. Free Radic. Biol. Med. 2019, 133, 162–168. [Google Scholar] [CrossRef] [PubMed]
  80. Ge, C.; Zhang, S.; Mu, H.; Zheng, S.; Tan, Z.; Huang, X.; Xu, C.; Zou, J.; Zhu, Y.; Feng, D.; et al. Emerging Mechanisms and Disease Implications of Ferroptosis: Potential Applications of Natural Products. Front. Cell Dev. Biol. 2022, 9, 774957. [Google Scholar] [CrossRef]
  81. Trachootham, D.; Alexandre, J.; Huang, P. Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nat. Rev. Drug Discov. 2009, 8, 579–591. [Google Scholar] [CrossRef] [PubMed]
  82. Amable, L. Cisplatin resistance and opportunities for precision medicine. Pharmacol. Res. 2016, 106, 27–36. [Google Scholar] [CrossRef] [PubMed]
  83. Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer 2013, 13, 714–726. [Google Scholar] [CrossRef] [PubMed]
  84. Yamaguchi, H.; Hsu, J.L.; Chen, C.-T.; Wang, Y.-N.; Hsu, M.-C.; Chang, S.-S.; Du, Y.; Ko, H.-W.; Herbst, R.; Hung, M.-C. Caspase-independent cell death is involved in the negative effect of egf receptor inhibitors on cisplatin in non–small cell lung cancer cells. Clin. Cancer Res. 2013, 19, 845–854. [Google Scholar] [CrossRef] [PubMed]
  85. Chen, L.; Li, X.; Liu, L.; Yu, B.; Xue, Y.; Liu, Y. Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function. Oncol. Rep. 2015, 33, 1465–1474. [Google Scholar] [CrossRef] [PubMed]
  86. Hassannia, B.; Vandenabeele, P.; Berghe, T.V. Targeting Ferroptosis to Iron Out Cancer. Cancer Cell 2019, 35, 830–849. [Google Scholar] [CrossRef] [PubMed]
  87. 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] [PubMed]
  88. 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]
  89. Orlando, U.D.; Castillo, A.F.; Dattilo, M.A.; Solano, A.R.; Maloberti, P.M.; Podesta, E.J. Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer. Oncotarget 2015, 6, 42632–42650. [Google Scholar] [CrossRef]
  90. Monaco, M.E.; Creighton, C.J.; Lee, P.; Zou, X.; Topham, M.K.; Stafforini, D.M. Expression of Long-chain Fatty Acyl-CoA Synthetase 4 in Breast and Prostate Cancers Is Associated with Sex Steroid Hormone Receptor Negativity. Transl. Oncol. 2010, 3, 91–98. [Google Scholar] [CrossRef]
  91. Chen, W.C.; Wang, C.Y.; Hung, Y.H.; Weng, T.Y.; Yen, M.C.; Lai, M.D. Systematic Analysis of Gene Expression Alterations and Clinical Outcomes for Long-Chain Acyl-Coenzyme A Synthetase Family in Cancer. PLoS ONE 2016, 11, e0155660. [Google Scholar] [CrossRef]
  92. 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. [Google Scholar] [CrossRef] [PubMed]
  93. Lang, X.; Green, M.D.; Wang, W.; Yu, J.; Choi, J.E.; Jiang, L.; Liao, P.; Zhou, J.; Zhang, Q.; Dow, A.; et al. Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis via Synergistic Repression of SLC7A11. Cancer Discov. 2019, 9, 1673–1685. [Google Scholar] [CrossRef] [PubMed]
  94. Lei, G.; Zhang, Y.; Koppula, P.; Liu, X.; Zhang, J.; Lin, S.H.; Ajani, J.A.; Xiao, Q.; Liao, Z.; Wang, H.; et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 2020, 30, 146–162. [Google Scholar] [CrossRef] [PubMed]
  95. Praticò, D.; Sung, S. Lipid peroxidation and oxidative imbalance: Early functional events in Alzheimer’s disease. J. Alzheimer’s Dis. 2004, 6, 171–175. [Google Scholar] [CrossRef] [PubMed]
  96. Belaidi, A.A.; Bush, A.I. Iron neurochemistry in Alzheimer’s disease and Parkinson’s disease: Targets for therapeutics. J. Neurochem. 2016, 139 (Suppl. 1), 179–197. [Google Scholar] [CrossRef] [PubMed]
  97. Raven, E.P.; Lu, P.H.; Tishler, T.A.; Heydari, P.; Bartzokis, G. Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer’s disease detected in vivo with magnetic resonance imaging. J. Alzheimer’s Dis. 2013, 37, 127–136. [Google Scholar] [CrossRef]
  98. Van Bergen, J.M.G.; Li, X.; Hua, J.; Schreiner, S.J.; Steininger, S.C.; Quevenco, F.C.; Wyss, M.; Gietl, A.F.; Treyer, V.; Leh, S.E.; et al. Colocalization of cerebral iron with Amyloid beta in Mild Cognitive Impairment. Sci. Rep. 2016, 6, 35514. [Google Scholar] [CrossRef]
  99. Rogers, J.T.; Bush, A.I.; Cho, H.H.; Smith, D.H.; Thomson, A.M.; Friedlich, A.L.; Lahiri, D.K.; Leedman, P.J.; Huang, X.; Cahill, C.M. Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: Riboregulation against neural oxidative damage in Alzheimer’s disease. Biochem Soc Trans. 2008, 36 Pt 6, 1282–1287. [Google Scholar] [CrossRef]
  100. Spotorno, N.; Acosta-Cabronero, J.; Stomrud, E.; Lampinen, B.; Strandberg, O.T.; van Westen, D.; Hansson, O. Relationship between cortical iron and tau aggregation in Alzheimer’s disease. Brain 2020, 143, 1341–1349. [Google Scholar] [CrossRef]
  101. Masaldan, S.; Bush, A.I.; Devos, D.; Rolland, A.S.; Moreau, C. Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration. Free Radic. Biol. Med. 2019, 133, 221–233. [Google Scholar] [CrossRef] [PubMed]
  102. Hambright, W.S.; Fonseca, R.S.; Chen, L.; Na, R.; Ran, Q. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 2017, 12, 8–17. [Google Scholar] [CrossRef] [PubMed]
  103. Zhang, Y.H.; Wang, D.W.; Xu, S.F.; Zhang, S.; Fan, Y.G.; Yang, Y.Y.; Guo, S.Q.; Wang, S.; Guo, T.; Wang, Z.Y.; et al. α-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice. Redox Biol. 2018, 14, 535–548. [Google Scholar] [CrossRef] [PubMed]
  104. Chen, J.J.; Thiyagarajah, M.; Song, J.; Chen, C.; Herrmann, N.; Gallagher, D.; Rapoport, M.J.; Black, S.E.; Ramirez, J.; Andreazza, A.C.; et al. Altered central and blood glutathione in Alzheimer’s disease and mild cognitive impairment: A meta-analysis. Alzheimer’s Res. Ther. 2022, 14, 23. [Google Scholar] [CrossRef] [PubMed]
  105. Ashraf, A.; Jeandriens, J.; Parkes, H.G.; So, P.W. Iron dyshomeostasis, lipid peroxidation and perturbed expression of cystine/glutamate antiporter in Alzheimer’s disease: Evidence of ferroptosis. Redox Biol. 2020, 32, 101494. [Google Scholar] [CrossRef] [PubMed]
  106. 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] [PubMed]
  107. Crouch, P.J.; Savva, M.S.; Hung, L.W.; Donnelly, P.S.; Mot, A.I.; Parker, S.J.; Greenough, M.A.; Volitakis, I.; Adlard, P.A.; Cherny, R.A.; et al. The Alzheimer’s therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity. J. Neurochem. 2011, 119, 220–230. [Google Scholar] [CrossRef]
  108. Grossi, C.; Francese, S.; Casini, A.; Rosi, M.C.; Luccarini, I.; Fiorentini, A.; Gabbiani, C.; Messori, L.; Moneti, G.; Casamenti, F. Clioquinol decreases amyloid-beta burden and reduces working memory impairment in a transgenic mouse model of Alzheimer’s disease. J. Alzheimer’s Dis. 2009, 2, 423–440. [Google Scholar] [CrossRef]
  109. Lin, G.; Zhu, F.; Kanaan, N.M.; Asano, R.; Shirafuji, N.; Sasaki, H.; Yamaguchi, T.; Enomoto, S.; Endo, Y.; Ueno, A.; et al. Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein. Int. J. Mol. Sci. 2021, 22, 12063. [Google Scholar] [CrossRef]
  110. Wang, T.; Wang, C.Y.; Shan, Z.Y.; Teng, W.P.; Wang, Z.Y. Clioquinol reduces zinc accumulation in neuritic plaques and inhibits the amyloidogenic pathway in AβPP/PS1 transgenic mouse brain. J. Alzheimer’s Dis. 2012, 3, 549–559. [Google Scholar] [CrossRef]
  111. Du, F.; Qian, Z.-M.; Luo, Q.; Yung, W.-H.; Ke, Y. Hepcidin Suppresses Brain Iron Accumulation by Downregulating Iron Transport Proteins in Iron-Overloaded Rats. Mol. Neurobiol. 2015, 52, 101–114. [Google Scholar] [CrossRef] [PubMed]
  112. Xu, Y.; Zhang, Y.; Zhang, J.-H.; Han, K.; Zhang, X.; Bai, X.; You, L.-H.; Yu, P.; Shi, Z.; Chang, Y.-Z.; et al. Astrocyte hepcidin ameliorates neuronal loss through attenuating brain iron deposition and oxidative stress in APP/PS1 mice. Free Radic. Biol. Med. 2020, 158, 84–95. [Google Scholar] [CrossRef] [PubMed]
  113. 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] [PubMed]
  114. Wu, L.; Liu, M.; Liang, J.; Li, N.; Yang, D.; Cai, J.; Zhang, Y.; He, Y.; Chen, Z.; Ma, T. Ferroptosis as a New Mechanism in Parkinson’s Disease Therapy Using Traditional Chinese Medicine. Front. Pharmacol. 2021, 12, 659584. [Google Scholar] [CrossRef] [PubMed]
  115. Ito, K.; Eguchi, Y.; Imagawa, Y.; Akai, S.; Mochizuki, H.; Tsujimoto, Y. MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells. Cell Death Discov. 2017, 3, 17013. [Google Scholar] [CrossRef] [PubMed]
  116. Pyatigorskaya, N.; Sharman, M.; Corvol, J.; Valabregue, R.; Yahia-Cherif, L.; Poupon, F.; Cormier-Dequaire, F.; Siebner, H.; Klebe, S.; Vidailhet, M.; et al. High Nigral Iron Deposition in LRRK2 and Parkin Mutation Carriers Using R2* Relaxometry. Mov. Disord. 2005, 30, 1077–1084. [Google Scholar] [CrossRef] [PubMed]
  117. Wu, C.; Zhao, W.; Yu, J.; Li, S.; Lin, L.; Chen, X. Induction of ferroptosis and mitochondrial dysfunction by oxidative stress in PC12 cells. Sci. Rep. 2018, 8, 574. [Google Scholar] [CrossRef] [PubMed]
  118. Angelova, P.R.; Choi, M.L.; Berezhnov, A.V.; Horrocks, M.H.; Hughes, C.D.; De, S.; Rodrigues, M.; Yapom, R.; Little, D.; Dolt, K.S.; et al. Alpha synuclein aggregation drives ferroptosis: An interplay of iron, calcium and lipid peroxidation. Cell Death Differ. 2020, 27, 2781–2796. [Google Scholar] [CrossRef]
  119. Devos, D.; Moreau, C.; Devedjian, J.C.; Kluza, J.; Petrault, M.; Laloux, C.; Jonneaux, A.; Ryckewaert, G.; Garçon, G.; Rouaix, N.; et al. Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid. Redox Signal. 2014, 21, 195–210. [Google Scholar] [CrossRef]
  120. Chen, X.; Li, D.; Sun, H.; Wang, W.; Wu, H.; Kong, W.; Kong, W. Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex. FEBS J. 2020, 287, 4747–4766. [Google Scholar] [CrossRef]
  121. MacDonald, M.E.; Ambrose, C.M.; Duyao, M.P.; Myers, R.H.; Lin, C.; Srinidhi, L.; MacFarlane, H.; Jenkins, B.; Anderson, M.A.; Wexler, N.S.; et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993, 72, 971–983. [Google Scholar] [CrossRef] [PubMed]
  122. Rosenblatt, A.; Liang, K.Y.; Zhou, H.; Abbott, M.H.; Gourley, L.M.; Margolis, R.L.; Brandt, J.; Ross, C.A. The association of CAG repeat length with clinical pro-gression in Huntington disease. Neurology 2006, 66, 1016–1020. [Google Scholar] [CrossRef]
  123. Ayala-Peña, S. Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis. Free Radic. Biol. Med. 2013, 62, 102–110. [Google Scholar] [CrossRef] [PubMed]
  124. Kumar, P.; Kalonia, H.; Kumar, A. Nitric oxide mechanism in the protective effect of antidepressants against 3-nitropropionic acid-induced cognitive deficit, glutathione and mitochondrial alterations in animal model of Huntington’s disease. Behav. Pharmacol. 2010, 21, 217–230. [Google Scholar] [CrossRef] [PubMed]
  125. Yang, W.S.; Stockwell, B.R. Ferroptosis: Death by Lipid Peroxidation. Trends Cell Biol. 2016, 26, 165–176. [Google Scholar] [CrossRef] [PubMed]
  126. Lee, J.; Kosaras, B.; Del Signore, S.J.; Cormier, K.; McKee, A.; Ratan, R.R.; Kowall, N.W.; Ryu, H. Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington’s disease mice. Acta Neuropathol. 2011, 121, 487–498. [Google Scholar] [CrossRef] [PubMed]
  127. Song, S.; Su, Z.; Kon, N.; Chu, B.; Li, H.; Jiang, X.; Luo, J.; Stockwell, B.R.; Gu, W. ALOX5-mediated ferroptosis acts as a distinct cell death pathway upon oxidative stress in Huntington’s disease. Genes Dev. 2023, 37, 204–217. [Google Scholar] [CrossRef]
  128. Sun, Q.Y.; Zhou, H.H.; Mao, X.Y. Emerging Roles of 5-Lipoxygenase Phosphorylation in Inflammation and Cell Death. Oxidative Med. Cell. Longev. 2019, 2019, 2749173. [Google Scholar] [CrossRef]
  129. Rosas, H.D.; Chen, Y.I.; Doros, G.; Salat, D.H.; Chen, N.K.; Kwong, K.K.; Bush, A.; Fox, J.; Hersch, S.M. Alterations in brain transition metals in Huntington disease: An evolving and intricate story. Arch Neurol. 2012, 69, 887–893. [Google Scholar] [CrossRef]
  130. Van Bergen, J.M.; Hua, J.; Unschuld, P.G.; Lim, I.A.; Jones, C.K.; Margolis, R.L.; Ross, C.A.; Van Zijl, P.C.; Li, X. Quantitative Susceptibility Mapping Suggests Altered Brain Iron in Premanifest Huntington Disease. AJNR Am. J. Neuroradiol. 2016, 37, 789–796. [Google Scholar] [CrossRef]
  131. Chen, J.; Marks, E.; Lai, B.; Zhang, Z.; Duce, J.A.; Lam, L.Q.; Volitakis, I.; Bush, A.I.; Hersch, S.; Fox, J.H. Iron accumulates in huntington’s disease neurons: Protection by deferoxamine. PLoS ONE 2013, 8, e77023. [Google Scholar] [CrossRef] [PubMed]
  132. Mi, Y.; Gao, X.; Xu, H.; Cui, Y.; Zhang, Y. The Emerging Roles of Ferroptosis in Huntington’s Disease. NeuroMole. Med. 2019, 21, 110–119. [Google Scholar] [CrossRef] [PubMed]
  133. Skouta, R.; Dixon, S.J.; Wang, J.; Dunn, D.E.; Orman, M.; Shimada, K.; Rosenberg, P.A.; Lo, D.C.; Weinberg, J.M.; Linkermann, A.; et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J. Am. Chem. Soc. 2014, 136, 4551–4556. [Google Scholar] [CrossRef] [PubMed]
  134. Yang, Y.; Zhang, J.; Liu, H.; Zhang, L. Change of Nrf2 expression in rat hippocampus in a model of chronic cerebral hypoperfusion. Int. J. Neurosci. 2014, 124, 577–584. [Google Scholar] [CrossRef] [PubMed]
  135. Rowland, L.P.; Shneider, N.A. Amyotrophic lateral sclerosis. N. Engl. J. Med. 2001, 344, 1688–1700. [Google Scholar] [CrossRef] [PubMed]
  136. Rosen, D.R.; Siddique, T.; Patterson, D.; Figlewicz, D.A.; Sapp, P.; Hentati, A.; Donaldson, D.; Goto, J.; O’Regan, J.P.; Deng, H.-X.; et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993, 362, 59–62. [Google Scholar] [CrossRef] [PubMed]
  137. Wang, T.; Tomas, D.; Perera, N.D.; Cuic, B.; Luikinga, S.; Viden, A.; Barton, S.K.; McLean, C.A.; Samson, A.L.; Southon, A.; et al. Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis. Cell Death Differ. 2022, 29, 1187–1198. [Google Scholar] [CrossRef]
  138. Kwan, J.Y.; Jeong, S.Y.; Van Gelderen, P.; Deng, H.-X.; Quezado, M.M.; Danielian, L.E.; Butman, J.A.; Chen, L.; Bayat, E.; Russell, J.; et al. Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: Correlating 7 tesla MRI and pathology. PLoS ONE 2012, 7, e35241. [Google Scholar] [CrossRef]
  139. Johnson, W.M.; Wilson-Delfosse, A.L.; Mieyal, J.J. Dysregulation of glutathione homeostasis in neurodegenerative diseases. Nutrients 2012, 4, 1399–1440. [Google Scholar] [CrossRef]
  140. Chen, L.; Na, R.; McLane, K.D.; Thompson, C.S.; Gao, J.; Wang, X.; Ran, Q. Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice. Sci. Rep. 2021, 11, 12890. [Google Scholar] [CrossRef]
  141. Devos, D.; Cabantchik, Z.I.; Moreau, C.; Danel, V.; Mahoney-Sanchez, L.; Bouchaoui, H.; Gouel, F.; Rolland, A.S.; Duce, J.A.; Devedjian, J.C. FAIRPARK-II and FAIRALS-II studygroups. Conservative iron chelation for neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis. J. Neural Transm. 2020, 127, 189–203. [Google Scholar] [CrossRef] [PubMed]
  142. Chen, L.; Hambright, W.S.; Na, R.; Ran, Q. Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis. J. Biol. Chem. 2015, 290, 28097–28106. [Google Scholar] [CrossRef] [PubMed]
  143. Hu, H.; Chen, Y.; Jing, L.; Zhai, C.; Shen, L. The Link Between Ferroptosis and Cardiovascular Diseases: A Novel Target for Treatment. Front. Cardiovasc. Med. 2021, 8, 710963. [Google Scholar] [CrossRef] [PubMed]
  144. Chen, Z.; Yan, Y.; Qi, C.; Liu, J.; Li, L.; Wang, J. The Role of Ferroptosis in Cardiovascular Disease and Its Therapeutic Significance. Front. Cardiovasc. Med. 2021, 8, 33229. [Google Scholar] [CrossRef] [PubMed]
  145. Fang, X.; Wang, H.; Han, D.; Xie, E.; Yang, X.; Wei, J.; Gu, S.; Gao, F.; Zhu, N.; Yin, X.; et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl. Acad. Sci. USA 2019, 116, 2672–2680. [Google Scholar] [CrossRef] [PubMed]
  146. Lakhal-Littleton, S.; Wolna, M.; Chung, Y.J.; Christian, H.C.; Heather, L.C.; Brescia, M.; Ball, V.; Diaz, R.; Santos, A.; Biggs, D.; et al. An essential cell-autonomous role for hepcidin in cardiac iron homeostasis. eLife 2016, 5, e19804. [Google Scholar] [CrossRef] [PubMed]
  147. Ward, D.M.; Kaplan, J. Ferroportin-mediated iron transport: Expression and regulation. Biochim. Biophys. Acta 2012, 1823, 1426–1433. [Google Scholar] [CrossRef]
  148. Lakhal-Littleton, S.; Wolna, M.; Carr, C.A.; Miller, J.J.J.; Christian, H.C.; Ball, V.; Santos, A.; Diaz, R.; Biggs, D.; Stillion, R.; et al. Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function. Proc. Natl. Acad. Sci. USA 2015, 112, 3164–3169. [Google Scholar] [CrossRef]
  149. Wang, H.; An, P.; Xie, E.; Wu, Q.; Fang, X.; Gao, H.; Zhang, Z.; Li, Y.; Wang, X.; Zhang, J.; et al. Characterization of ferroptosis in murine models of hemochromatosis. Hepatology 2017, 66, 449–465. [Google Scholar] [CrossRef]
  150. Gao, M.; Monian, P.; Quadri, N.; Ramasamy, R.; Jiang, X. Glutaminolysis and Transferrin Regulate Ferroptosis. Mol. Cell 2015, 59, 298–308. [Google Scholar] [CrossRef]
  151. Sanada, S.; Komuro, I.; Kitakaze, M. Pathophysiology of myocardial reperfusion injury: Preconditioning, postconditioning, and translational aspects of protective measures. Am. J. Physiol. Heart Circ. Physiol 2011, 301, H1723–H1741. [Google Scholar] [CrossRef] [PubMed]
  152. Jones, C.E.; Thomas, J.X.; Parker, J.C.; Parker, R.E. Acute changes in high energy phosphates, nucleotide derivatives, and contractile force in ischaemic and nonischaemic canine myocardium following coronary occlusion. Cardiovasc. Res. 1976, 10, 275–282. [Google Scholar] [CrossRef] [PubMed]
  153. Tóth, O.M.; Menyhárt, A.; Frank, R.; Hantosi, D.; Farkas, E.; Bari, F. Tissue Acidosis Associated with Ischemic Stroke to Guide Neuroprotective Drug Delivery. Biology 2020, 9, 460. [Google Scholar] [CrossRef] [PubMed]
  154. Baloglu, E. Hypoxic Stress-Dependent Regulation of Na,K-ATPase in Ischemic Heart Disease. Int. J. Mol. Sci. 2023, 24, 7855. [Google Scholar] [CrossRef] [PubMed]
  155. Granger, D.N.; Kvietys, P.R. Reperfusion injury and reactive oxygen species: The evolution of a concept. Redox Biol. 2015, 6, 524–551. [Google Scholar] [CrossRef] [PubMed]
  156. Danton, G.H.; Dietrich, W.D. Inflammatory mechanisms after ischemia and stroke. J. Neuropathol. Exp. Neurol. 2003, 62, 127–136. [Google Scholar] [CrossRef] [PubMed]
  157. Chen, D.; Wang, C.; Yu, H.; Liu, G.; Qian, B.; Chen, B.; Li, Z.; Zhou, Y.; Pan, S.; Li, B.; et al. Nitrogen-Doped Carbon Dots with Oxidation Stress Protective Effects for Reactive Oxygen Species Scavenging on Hepatic Ischemia–Reperfusion Injury. ACS Appl. Nano Mater. 2023, 6, 13155–13165. [Google Scholar] [CrossRef]
  158. Wu, J.R.; Tuo, Q.Z.; Lei, P. Ferroptosis, a Recent Defined Form of Critical Cell Death in Neurological Disorders. J. Mol. Neurosci. 2018, 66, 197–206. [Google Scholar] [CrossRef]
  159. Bulluck, H.; Rosmini, S.; Abdel-Gadir, A.; White, S.K.; Bhuva, A.N.; Treibel, T.A.; Fontana, M.; Ramlall, M.; Hamarneh, A.; Sirker, A.; et al. Residual Myocardial Iron Following Intramyocardial Hemorrhage During the Convalescent Phase of Reperfused ST-Segment-Elevation Myocardial Infarction and Adverse Left Ventricular Remodeling. Circ. Cardiovasc. Imaging 2016, 9, e004940. [Google Scholar] [CrossRef]
  160. Linkermann, A. Nonapoptotic cell death in acute kidney injury and transplantation. Kidney Int. 2016, 89, 46–57. [Google Scholar] [CrossRef]
  161. Pefanis, A.; Ierino, F.L.; Murphy, J.M.; Cowan, P.J. Regulated necrosis in kidney ischemia-reperfusion injury. Kidney Int. 2019, 96, 291–301. [Google Scholar] [CrossRef] [PubMed]
  162. 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]
  163. 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] [PubMed]
  164. Zhao, Y.; Li, Y.; Zhang, R.; Wang, F.; Wang, T.; Jiao, Y. The Role of Erastin in Ferroptosis and Its Prospects in Cancer Therapy. OncoTargets Ther. 2020, 3, 5429–5441. [Google Scholar] [CrossRef] [PubMed]
  165. 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] [PubMed]
  166. Zhang, X.; Guo, Y.; Li, H.; Han, L. FIN56, a novel ferroptosis inducer, triggers lysosomal membrane permeabilization in a TFEB-dependent manner in glioblastoma. J. Cancer 2021, 12, 6610–6619. [Google Scholar] [CrossRef] [PubMed]
  167. Shimada, K.; Stockwell, B.R. tRNA synthase suppression activates de novo cysteine synthesis to compensate for cystine and glutathione deprivation during ferroptosis. Mol. Cell Oncol. 2015, 3, e1091059. [Google Scholar] [CrossRef]
  168. Sun, Y.; Berleth, N.; Wu, W.; Schlütermann, D.; Deitersen, J.; Stuhldreier, F.; Berning, L.; Friedrich, A.; Akgün, S.; Mendiburo, M.J.; et al. Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells. Cell Death Dis. 2021, 12, 1028. [Google Scholar] [CrossRef]
  169. Shimada, K.; Skouta, R.; Kaplan, A.; Yang, W.S.; Hayano, M.; Dixon, S.J.; Brown, L.M.; A Valenzuela, C.; 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]
  170. Zhang, W.; Jiang, B.; Liu, Y.; Xu, L.; Wan, M. Bufotalin induces ferroptosis in non-small cell lung cancer cells by facilitating the ubiquitination and degradation of GPX4. Free Radic. Biol. Med. 2022, 180, 75–84. [Google Scholar] [CrossRef]
  171. Yang, L.; Chen, X.; Yang, Q.; Chen, J.; Huang, Q.; Yao, L.; Yan, D.; Wu, J.; Zhang, P.; Tang, D.; et al. Broad Spectrum Deubiquitinase Inhibition Induces Both Apoptosis and Ferroptosis in Cancer Cells. Front. Oncol. 2020, 10, 949. [Google Scholar] [CrossRef] [PubMed]
  172. Yao, X.; Zhang, Y.; Hao, J.; Duan, H.-Q.; Zhao, C.-X.; Sun, C.; Li, B.; Fan, B.-Y.; Li, W.-X.; Fu, X.-H.; et al. Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis. Neural Regen. Res. 2019, 14, 532–541. [Google Scholar] [PubMed]
  173. Kwiatkowski, J.L.; Hamdy, M.; El-Beshlawy, A.; Ebeid, F.S.E.; Badr, M.; AlShehri, A.A.M.; Kanter, J.; Inusa, B.D.P.; Adly, A.A.M.; Williams, S.; et al. Deferiprone vs. deferoxamine for transfusional iron overload in SCD and other anemias: A randomized, open-label noninferiority study. Blood Adv. 2022, 6, 1243–1254. [Google Scholar] [CrossRef] [PubMed]
  174. Rayatpour, A.; Foolad, F.; Heibatollahi, M.; Khajeh, K.; Javan, M. Ferroptosis inhibition by deferiprone, attenuates myelin damage and promotes neuroprotection in demyelinated optic nerve. Sci. Rep. 2022, 12, 19630. [Google Scholar] [CrossRef] [PubMed]
  175. Miotto, G.; Rossetto, M.; Di Paolo, M.L.; Orian, L.; Venerando, R.; Roveri, A.; Vučković, A.-M.; Travain, V.B.; Zaccarin, M.; Zennaro, L.; et al. Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol. 2020, 28, 101328. [Google Scholar] [CrossRef] [PubMed]
  176. Tong, J.; Lan, X.T.; Zhang, Z.; Liu, Y.; Sun, D.Y.; Wang, X.J.; Ou-Yang, S.X.; Zhuang, C.L.; Shen, F.M.; Wang, P.; et al. Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: Potential involvement of PANoptosis. Acta Pharmacol. Sin. 2023, 44, 1014–1028. [Google Scholar] [CrossRef] [PubMed]
  177. Li, Y.; Sun, M.; Cao, F.; Chen, Y.; Zhang, L.; Li, H.; Cao, J.; Song, J.; Ma, Y.; Mi, W.; et al. The Ferroptosis Inhibitor Liproxstatin-1 Ameliorates LPS-Induced Cognitive Impairment in Mice. Nutrients 2022, 14, 4599. [Google Scholar] [CrossRef] [PubMed]
  178. Yao, X.; Feng, S.-Q.; Fan, B.-Y.; Pang, Y.-L.; Li, W.-X.; Zhao, C.-X.; Zhang, Y.; Wang, X.; Ning, G.-Z.; Kong, X.-H.; et al. Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4. Neural Regen. Res. 2021, 16, 561–566. [Google Scholar] [CrossRef]
  179. Stepanić, V.; Kučerová-Chlupáčová, M. Review and Chemoinformatic Analysis of Ferroptosis Modulators with a Focus on Natural Plant Products. Molecules 2023, 28, 475. [Google Scholar] [CrossRef]
  180. Zheng, K.; Dong, Y.; Yang, R.; Liang, Y.; Wu, H.; He, Z. Regulation of ferroptosis by bioactive phytochemicals: Implications for medical nutritional therapy. Pharmacol. Res. 2021, 168, 105580. [Google Scholar] [CrossRef]
  181. El Hajj, S.; Canabady-Rochelle, L.; Gaucher, C. Nature-Inspired Bioactive Compounds: A Promising Approach for Ferroptosis-Linked Human Diseases? Molecules 2023, 28, 2636. [Google Scholar] [CrossRef] [PubMed]
  182. Liu, Y.; Yang, S.; Wang, K.; Lu, J.; Bao, X.; Wang, R.; Qiu, Y.; Wang, T.; Yu, H. Cellular senescence and cancer: Focusing on traditional Chinese medicine and natural products. Cell Prolif. 2020, 53, 5995–6003. [Google Scholar] [CrossRef] [PubMed]
  183. Slezakova, S.; Ruda-Kucerova, J. Anticancer Activity of Artemisinin and its Derivatives. Anticancer Res. 2017, 37, 5995–6003. [Google Scholar] [PubMed]
  184. Wang, J.; Xu, C.; Wong, Y.K.; Li, Y.; Liao, F.; Jiang, T.; Tu, Y. Artemisinin, the Magic Drug Discovered from Traditional Chinese Medicine. Engineering 2019, 5, 32–39. [Google Scholar] [CrossRef]
  185. Kalen, A.L.; Wagner, B.A.; Sarsour, E.H.; Kumar, M.G.; Reedy, J.L.; Buettner, G.R.; Barua, N.C.; Goswami, P.C. Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Car-ba-Dimer-Induced Toxicity of Human Cancer Cells. Antioxidants 2020, 9, 108. [Google Scholar] [CrossRef] [PubMed]
  186. Wu, Z.; Zhong, M.; Liu, Y.; Xiong, Y.; Gao, Z.; Ma, J.; Zhuang, G.; Hong, X. Application of natural products for inducing ferroptosis in tumor cells. Biotechnol. Appl. Biochem. 2022, 69, 190–197. [Google Scholar] [CrossRef] [PubMed]
  187. Wu, X.; Zhou, Q.H.; Xu, K. Are isothiocyanates potential anti-cancer drugs? Acta Pharmacol. Sin. 2009, 30, 501–512. [Google Scholar] [CrossRef]
  188. Gupta, P.; Wright, S.E.; Kim, S.-H.; Srivastava, S.K. Phenethyl isothiocyanate: A comprehensive review of anti-cancer mechanisms. Biochim. Biophys. Acta 2014, 1846, 405–424. [Google Scholar] [CrossRef]
  189. Kasukabe, T.; Honma, Y.; Okabe-Kado, J.; Higuchi, Y.; Kato, N.; Kumakura, S. Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells. Oncol. Rep. 2016, 36, 968–976. [Google Scholar] [CrossRef]
  190. Ding, W.; Lin, L.; Yue, K.; He, Y.; Xu, B.; Shaukat, A.; Huang, S. Ferroptosis as a Potential Therapeutic Target of Traditional Chinese Medicine for Mycotoxicosis: A Review. Toxics 2023, 11, 395. [Google Scholar] [CrossRef]
  191. Cascão, R.; Vidal, B.; Raquel, H.; Neves-Costa, A.; Figueiredo, N.; Gupta, V.; Fonseca, J.E.; Moita, L.F. Potent anti-inflammatory and antiproliferative effects of gambogic acid in a rat model of antigen-induced arthritis. Mediat. Inflamm. 2014, 2014, 195327. [Google Scholar] [CrossRef] [PubMed]
  192. Seo, M.J.; Lee, D.M.; Kim, I.Y.; Lee, D.; Choi, M.-K.; Lee, J.-Y.; Park, S.S.; Jeong, S.-Y.; Choi, E.K.; Choi, K.S. Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis. Cell Death Dis. 2019, 10, 187. [Google Scholar] [CrossRef] [PubMed]
  193. Liu, Y.; Chen, Y.; Lin, L.; Li, H. Gambogic Acid as a Candidate for Cancer Therapy: A Review. Int. J. Nanomed. 2020, 15, 10385–10399. [Google Scholar] [CrossRef] [PubMed]
  194. Mishra, D.; Jain, N.; Rajoriya, V.; Jain, A.K. Glycyrrhizin conjugated chitosan nanoparticles for hepatocyte-targeted delivery of lamivudine. J. Pharm. Pharmacol. 2014, 66, 1082–1093. [Google Scholar] [CrossRef] [PubMed]
  195. Nazari, S.; Rameshrad, M.; Hosseinzadeh, H. Toxicological Effects of Glycyrrhiza glabra (Licorice): A Review. Phytother. Res. 2017, 31, 1635–1650. [Google Scholar] [CrossRef] [PubMed]
  196. Wang, Y.; Chen, Q.; Shi, C.; Jiao, F.; Gong, Z. Mechanism of glycyrrhizin on ferroptosis during acute liver failure by inhibiting oxidative stress. Mol. Med. Rep. 2019, 20, 4081–4090. [Google Scholar] [CrossRef] [PubMed]
  197. Chen, Y.; Fang, Z.M.; Yi, X.; Wei, X.; Jiang, D.S. The interaction between ferroptosis and inflammatory signalling pathways. Cell Death Dis. 2023, 14, 205. [Google Scholar] [CrossRef] [PubMed]
  198. 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]
  199. Li, Q.; Liao, J.; Chen, W.; Zhang, K.; Li, H.; Ma, F.; Zhang, H.; Han, Q.; Guo, J.; Li, Y.; et al. NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway. Free Radic. Biol. Med. 2022, 187, 158–170. [Google Scholar] [CrossRef]
  200. Karuppagounder, S.S.; Alin, L.; Chen, Y.; Brand, D.; Bourassa, M.W.; Dietrich, K.; Wilkinson, C.M.; Nadeau, C.A.; Kumar, A.; Perry, S.; et al. N-acetylcysteine targets 5 lipoxygenase-derived, toxic lipids and can synergize with prostaglandin E2 to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice. Ann. Neurol. 2018, 84, 854–872. [Google Scholar] [CrossRef]
  201. Rasouli, H.; Farzaei, M.H.; Khodarahmi, R. Polyphenols and their benefits: A review. Int. J. Food Prop. 2017, 20, 1700–1741. [Google Scholar] [CrossRef]
  202. Russo, C.; Maugeri, A.; Lombardo, G.E.; Musumeci, L.; Barreca, D.; Rapisarda, A.; Cirmi, S.; Navarra, M. The Second Life of Citrus Fruit Waste: A Valuable Source of Bioactive Compounds. Molecules 2021, 26, 5991. [Google Scholar] [CrossRef]
  203. Zilka, O.; Shah, R.; Li, B.; Angeli, J.P.F.; Griesser, M.; Conrad, M.; Pratt, D.A. On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death. ACS Cent. Sci. 2017, 3, 232–243. [Google Scholar] [CrossRef]
  204. Wei, Z.; Shaohuan, Q.; Pinfang, K.; Chao, S. Curcumin Attenuates Ferroptosis-Induced Myocardial Injury in Diabetic Cardiomyopathy through the Nrf2 Pathway. Cardiovasc. Ther. 2022, 2022, 3159717. [Google Scholar] [CrossRef] [PubMed]
  205. Guerrero-Hue, M.; García-Caballero, C.; Palomino-Antolín, A.; Rubio-Navarro, A.; Vázquez-Carballo, C.; Herencia, C.; Martín-Sanchez, D.; Farré-Alins, V.; Egea, J.; Cannata, P.; et al. Curcumin reduces renal damage associated with rhabdomyolysis by decreasing ferroptosis-mediated cell death. FASEB J. 2019, 33, 8961–8975. [Google Scholar] [CrossRef]
  206. Kose, T.; Vera-Aviles, M.; Sharp, P.A.; Latunde-Dada, G.O. Curcumin and (-)- Epigallocatechin-3-Gallate Protect Murine MIN6 Pancreatic Beta-Cells Against Iron Toxicity and Erastin-Induced Ferroptosis. Pharmaceuticals 2019, 12, 26. [Google Scholar] [CrossRef] [PubMed]
  207. Yang, C.; Wu, A.; Tan, L.; Tang, D.; Chen, W.; Lai, X.; Gu, K.; Chen, J.; Chen, D.; Tang, Q. Epigallocatechin-3-Gallate Alleviates Liver Oxidative Damage Caused by Iron Overload in Mice through Inhibiting Ferroptosis. Nutrients 2023, 15, 1993. [Google Scholar] [CrossRef]
  208. Shao, C.; Yuan, J.; Liu, Y.; Qin, Y.; Wang, X.; Gu, J.; Chen, G.; Zhang, B.; Liu, H.K.; Zhao, J.; et al. Epileptic brain fluorescent imaging reveals apigenin can relieve the myeloperoxidase-mediated oxidative stress and inhibit ferroptosis. Proc. Natl. Acad. Sci. USA 2020, 117, 10155–10164. [Google Scholar] [CrossRef]
  209. Polera, N.; Badolato, M.; Perri, F.; Carullo, G.; Aiello, F. Quercetin and its Natural Sources in Wound Healing Management. Curr. Med. Chem. 2019, 26, 5825–5848. [Google Scholar] [CrossRef]
  210. Xiao, L.; Luo, G.; Tang, Y.; Yao, P. Quercetin and iron metabolism: What we know and what we need to know. Food Chem. Toxicol. 2018, 114, 190–203. [Google Scholar] [CrossRef]
  211. Li, X.; Zeng, J.; Liu, Y.; Liang, M.; Liu, Q.; Li, Z.; Zhao, X.; Chen, D. Inhibitory Effect and Mechanism of Action of Quercetin and Quercetin Diels-Alder anti-Dimer on Erastin-Induced Ferroptosis in Bone Marrow-Derived Mesenchymal Stem Cells. Antioxidants 2020, 9, 205. [Google Scholar] [CrossRef]
  212. Xie, Y.; Song, X.; Sun, X.; Huang, J.; Zhong, M.; Lotze, M.T.; Zeh, H.J.R.; Kang, R.; Tang, D. Identification of baicalein as a ferroptosis inhibitor by natural product library screening. Biochem. Biophys. Res. Commun. 2016, 473, 775–780. [Google Scholar] [CrossRef]
Figure 1. Ferroptosis pathway. Ferroptosis may be triggered by transferrin endocytosis linked to transferrin receptor 1 (TfR1). After endocytosis, transferrin releases Fe3+ which is reduced in Fe2+. Ferrous iron-mediated Fenton reaction increases ROS such as hydroxyl radical that react with membrane lipids inducing lipid peroxidation. Lipid peroxidation is also alimented via LOX action which oxidizes PUFA, generating the corresponding hydroperoxide derivatives which, in turn, react with other membrane lipids. Lipid peroxidation may be regulated by GPx4, which converts hydroperoxides in H2O and lipid peroxides into their respective alcohols via oxidation of GSH into its disulfide form GSSG. GSH levels are maintained by system Xc, which mediates the exchange of extracellular glutamate and intracellular cystine required for its synthesis.
Figure 1. Ferroptosis pathway. Ferroptosis may be triggered by transferrin endocytosis linked to transferrin receptor 1 (TfR1). After endocytosis, transferrin releases Fe3+ which is reduced in Fe2+. Ferrous iron-mediated Fenton reaction increases ROS such as hydroxyl radical that react with membrane lipids inducing lipid peroxidation. Lipid peroxidation is also alimented via LOX action which oxidizes PUFA, generating the corresponding hydroperoxide derivatives which, in turn, react with other membrane lipids. Lipid peroxidation may be regulated by GPx4, which converts hydroperoxides in H2O and lipid peroxides into their respective alcohols via oxidation of GSH into its disulfide form GSSG. GSH levels are maintained by system Xc, which mediates the exchange of extracellular glutamate and intracellular cystine required for its synthesis.
Ijms 24 17279 g001
Figure 2. Ferroptosis-related diseases and pathophysiological implications. Ferroptosis can be associated with different diseases affecting different body districts, such as nervous system, digestive system, respiratory system, circulatory system, urinary system, and immune system.
Figure 2. Ferroptosis-related diseases and pathophysiological implications. Ferroptosis can be associated with different diseases affecting different body districts, such as nervous system, digestive system, respiratory system, circulatory system, urinary system, and immune system.
Ijms 24 17279 g002
Table 1. The main features of Ferroptosis, Necroptosis, Apoptosis, Autophagy, and Pyroptosis.
Table 1. The main features of Ferroptosis, Necroptosis, Apoptosis, Autophagy, and Pyroptosis.
Cell morphologySwelling, reduction of mithocondrial cristaeSwellingShrinkage, intercellular junction disappearenceVescicles in cytoplasm, autophagosome formationSwelling, bubbling[1,2,4]
MembraneRupture plasma membraneMembrane blebbingRupture plasma membrane[1,4]
NucleusPyknosis, Karyorrhexis, KaryolysisChromatine condensation and nuclear disintegration Chromatine condensation[1,4]
Biochemical featuresIron and ROS accumulation, GSH depletion, lipid peroxidationLower ATP levelCaspase 3, 6, 7 activation Caspase 1, 4, 5, 11 activation[1,2,4]
Table 2. Natural and synthetic inhibitors of ferroptosis.
Table 2. Natural and synthetic inhibitors of ferroptosis.
DrugsNature of the CompoundTargetsTest ModelsFunctionsReferences
DeferoxamineSyntheticIronHT-1080; Calu-1; BJeLR; PC12; MEF cells; Aging model miceIron chelation; ROS generation inhibition; Lipid peroxidation inhibition [2,17,152,155]
Deferiprone (DFP)SyntheticIronPatients with iron overloadIron chelation; ROS generation inhibition [153]
Ferrostatin-1Synthetic15-LOX/PEBP1HT-1080 cellsFree radical scavenger; Lipid peroxidation inhibition[158,159]
Lipro-1SyntheticOLN-93 cell lineLipid peroxidation inhibition; GPx4 expression improved; GSH levels increase [145,159,160]
Glycyrrhizin (GLY)NaturalHMGB1/GPx4
HepatocytesLipid peroxidation inhibition[173,174,175]
CryptotanshinoneNaturalSTAT3PDAC cell lines Silencing STAT3[133]
N-acetylcysteineNaturalJAK-STAT pathwayICH model mice and ratsGSH increase; ROS generation inhibition; Lipid peroxidation inhibition[75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176]
CurcuminNaturalIronMouse models; Mouse insulinoma pancreatic cells (MIN6)GPx4 increased expression; Lipid peroxidation inhibition; Iron chelation[179,180,181,182]
Epigallocatechin gallate (EGCG)NaturalIronMouse insulinoma pancreatic cells (MIN6)Iron chelation; Lipid peroxidation inhibition[181,182,183]
ApigeninNaturalGPx4; SIRT1Human neuroblastoma SH-SY5Y cellsROS generation inhibition; GPx4 and SIRT1 induction[184]
QuercetinNaturalIronMouse cellsLipid peroxidation inhibition; Iron chelation[185,186,187]
BaicaleinNaturalGPx4; Nrf2Human pancreatic cancer cells (BxPc3); Epithelioid carcinoma cells (PANC1)ROS generation inhibition; Lipid peroxidation inhibition[188]
Table 3. Natural and synthetic inducers of ferroptosis.
Table 3. Natural and synthetic inducers of ferroptosis.
DrugsNature of the CompoundTargetsTest ModelsFunctionsReferences
RSL-3SyntheticGPx4Cancer cellsGPx4 inhibition; ROS generation inhibition[137,138,139]
ErastinSyntheticSystem Xc; VDAC2;Cancer cellsVDAC2 inhibition; System Xc inhibition; GSH reduction[140,141,142,143,144,145]
FIN56SyntheticGPx4Cancer cellsGPx4 depletion; Squalene synthase activation[146,147,148,149,150]
ArtemisininNaturalIronCancer cellsROS generation Lipid peroxidation increase[2,164,165,166]
Isothiocyanates (ITCs)NaturalIron MAPK signaling pathwayCancer cellsROS generation[167,168,169]
Gambogic acid (GA)NaturalThioredoxin systemCancer cellsROS generation[170,171,172,173]
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.

Share and Cite

MDPI and ACS Style

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.

AMA Style

Patanè GT, 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. International Journal of Molecular Sciences. 2023; 24(24):17279.

Chicago/Turabian Style

Patanè, Giuseppe Tancredi, Stefano Putaggio, Ester Tellone, Davide Barreca, Silvana Ficarra, Carlo Maffei, Antonella Calderaro, and Giuseppina Laganà. 2023. "Ferroptosis: Emerging Role in Diseases and Potential Implication of Bioactive Compounds" International Journal of Molecular Sciences 24, no. 24: 17279.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop