Search Results (124)

Background Aflatoxin B1 (AFB1) is a potent hepatotoxic mycotoxin that induces severe oxidative liver damage. Kaempferol (Kae), a natural flavonoid with known antioxidant properties, has unclear protective effects against AFB1-induced hepatotoxicity. This study aimed to evaluate the hepatoprotective role of Kae and elucidate its underlying mechanism using integrated in vivo, in silico, and in vitro approaches. Methods: In vivo (AFB1-challenged mice) and in vitro (hepatocyte) models were employed, combined with network pharmacology, molecular docking, and molecular dynamics simulations. Liver injury indices, oxidative stress markers, antioxidant enzyme activities, and Keap1/Nrf2 pathway expression were assessed. Results: Kae co-treatment reversed AFB1-induced increases in liver index, serum ALT/AST, histological lesions, and reduced antioxidant capacity in mice. Network pharmacology revealed 59 common targets, with NFE2L2 (Nrf2) as a key node. In vitro, Kae pretreatment significantly lowered AFB1-elevated ROS, MDA, ALT, and AST, while restoring GSH and total antioxidant capacity. Kae reversed AFB1-induced Keap1 upregulation and Nrf2 downregulation, and increased mRNA levels of HO-1, NQO1, SOD, GPX1, and CAT. Molecular docking and simulation showed stable Kae–Keap1 binding (−9.6 kcal/mol) with critical hydrogen bonds (VAL-606) and van der Waals contacts. Conclusions: Kae directly binds Keap1, activates Nrf2 signaling, upregulates antioxidant gene expression, and mitigates AFB1-induced oxidative liver injury. These findings support Kae as a promising candidate for preventing AFB1 hepatotoxicity. Full article

Aging is a significant risk factor for cardiovascular diseases. The prevalence of heart failure increases with age, making it a leading cause of morbidity and mortality. We investigated age-associated changes in expression of Nuclear Factor (Erythroid-derived 2)-Like 2 (NFE2L2 or NRF2) in the myocardium of humans, rhesus monkeys, Fischer rats, and C57BL/6 mice. NRF2 is a transcription factor that orchestrates the expression of genes involved in antioxidant and detoxification responses. Analyses of RNA-seq data from the Genotype-Tissue Expression (GTEx) project, which contains left ventricular samples from 294 male donors, revealed a trend of age-associated declines in NRF2 transcripts and several of its downstream genes (SOD1, SOD2, CAT, GCLM, and AKR1B). Age-dependent decreases in NRF2 protein expression were observed in the myocardium of Rhesus monkeys and Fischer rats. To determine whether NRF2 loss contributes to myocardial aging, we evaluated cardiac function of NRF2 knockout mice (KO) at 19 and 24 months of age. At 19 months, the NRF2 KO mice exhibited diastolic dysfunction, characterized by an increased end-diastolic volume (EDV) and end-systolic volume (ESV), accompanied by a reduced ejection fraction (EF) and fractional shortening (FS), indicative of early onset of heart failure. The NRF2 KO mice displayed premature aging phenotypes and had reduced lifespans. Our findings support the trend of NRF2 signaling decline with age, and that loss of NRF2 accelerates the maladaptive cardiac remodeling and functional deterioration associated with aging. Full article

Tamoxifen remains the standard treatment for estrogen receptor alpha (ER α) positive breast cancer (BC) cases. However, a significant proportion of patients develop chemoresistance, leading to disease recurrence. The Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), coded by NFE2L2 gene, has emerged as a key player in chemoresistance and tumoral progression across multiple cancer types, including BC. This study aimed to analyze the role of Nrf2 in metastasis-related processes in a tamoxifen-metabolite-resistant BC cell variant (MCF-7^Var-H) and to assess the impact of Nrf2 modulation. We analyzed Nrf2 expression and nuclear localization and observed that both were increased in endocrine-chemoresistant MCF-7^Var-H cells compared with MCF-7 parental cells. Critically, we assessed the effects of Nrf2 on migration, invasion, and metalloproteinase secretion capacity using wound-healing assays, Boyden chamber assays, and zymography, respectively. Our results suggest that Nrf2 actively promotes metastatic behaviors in the resistant variant. To further explore its pharmacological relevance, we designed and synthesized small interfering RNAs (siRNAs) targeting NFE2L2 mRNA in its coding region by heterogeneous-phase chemical synthesis. Transfection with these siRNAs significantly inhibited metastasis-related functions such as migration in MCF-7^Var-H cells. Overall, siRNAs targeting Nrf2 may be promising tools for treating chemoresistant and metastatic breast cancer. Full article

Background: Esophageal squamous cell carcinoma (ESCC) remains a highly lethal malignancy with limited therapeutic options, in part due to frequent activation of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). Gain-of-function mutations in NRF2 disrupt its negative regulation by Kelch-like ECH-associated protein 1 (KEAP1), resulting in sustained NRF2 signaling that promotes tumor growth and resistance to chemotherapy and radiation. We previously identified the FDA-approved drug pyrimethamine (PYR) as an NRF2 inhibitor and demonstrated that inhibition of dihydrofolate reductase (DHFR) represents the primary mechanism underlying its NRF2-suppressive activity, supporting its advancement into a Phase I window-of-opportunity clinical trial (NCT 05678348). Meanwhile, in NRF2^W24C-KYSE70 and NRF2^D77V-KYSE180 cells, PYR promoted NRF2^Mut ubiquitination and proteasomal degradation and shortened its half-life. This study aims to explore additional modes of action by which PYR inhibits NRF2. Methods: Cell cycle analysis was performed by flow cytometry. Cell proliferation, apoptosis and chemosensitivity were assessed by Live-Cell Analysis System, while radiosensitivity was evaluated using X-ray irradiation and the CellTiter-Glo assay. Molecular interactions between NRF2 and KEAP1 were examined through Co-IP and PLA, and the direct binding of PYR to KEAP1 was quantified using ITC and SPR. Molecular docking and dynamic simulations were employed to predict potential PYR-binding pockets within the Kelch domain. Results: Using genetically defined isogenic ESCC cell models, we show that activation of mutant NRF2 (NRF2^Mut) or wild-type NRF2 (NRF2^WT) produces distinct, context-dependent effects on squamous differentiation, proliferation, and therapeutic response. We further demonstrate that PYR restores sensitivity to chemotherapy and ionizing radiation in NRF2^Mut ESCC cells. Mechanistically, short-term PYR treatment promotes KEAP1-dependent proteasome-mediated degradation of NRF2^W24C. Biochemical and biophysical assays indicate that PYR enhances the interaction between KEAP1 and NRF2^W24C in a manner associated with KEAP1-dependent proteasomal degradation. Computational modeling further suggests that PYR may engage a pocket within the Kelch domain to facilitate the NRF2^W24C-KEAP1 interaction. Conclusions: These findings show that PYR functionally restores KEAP1-mediated NRF2 degradation of select NRF2^Mut through a glue-like effect and overcomes therapy resistance in ESCC. Although the proposed glue-like mechanism remains hypothetical, this work supports further investigation into the NRF2–KEAP1 interaction and may inform the development of KEAP1-targeted strategies for NRF2^Mut cancers, including ESCC. Full article

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and oxidative stress, increasingly implicated in cancer biology. However, its molecular regulation across breast cancer subtypes and its potential systemic manifestations remain incompletely understood. The aim of this study was to identify ferroptosis-associated molecular alterations that are largely shared across subtypes and to evaluate their systemic reflection following localized tissue injury. Tumor and matched normal breast tissues representing major molecular subtypes were analyzed. Global mRNA and miRNA expression profiling was performed using microarrays, followed by validation of selected genes using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Functional enrichment and protein–protein interaction analyses were conducted to characterize associated pathways. In addition, systemic responses were assessed in patients undergoing fibroadenoma cryoablation through longitudinal blood sampling. Six ferroptosis-related genes (SLC7A11, GPX4, FTH1, NQO1, NFE2L2, SQSTM1) demonstrated consistent upregulation across all breast cancer subtypes, with higher expression observed in more aggressive tumors. These genes are functionally linked to antioxidant defense, iron metabolism, and oxidative stress regulation, and their coordinated expression pattern is consistent with activation of NRF2-dependent cytoprotective pathways. Downregulation of selected miRNAs may contribute to this expression profile but likely represents a secondary regulatory mechanism. Survival analysis revealed heterogeneous and subtype-dependent associations, with limited and gene-specific prognostic relevance. Cryoablation induced transient increases in circulating levels of the analyzed proteins, reflecting systemic responses to localized tissue injury. In conclusion, breast cancer is characterized by a largely shared ferroptosis-associated molecular signature across subtypes; however, its clinical impact appears to be variable and context-dependent. Systemic detection of related molecular signals suggests potential utility as indicators of tissue stress responses, although their role as specific biomarkers of ferroptosis requires further validation. Full article

MYO16 has previously been identified as a candidate gene in studies of meat productivity in sheep, but its complete sequence and the potential impact of polymorphisms on the functional properties of the gene in sheep remain understudied. The aim of this study was to analyze genetic variation in the MYO16 gene region in sheep and to identify polymorphisms that, according to bioinformatic prediction, are capable of changing the amino acid sequence of the protein or are associated with allele-specific differences in transcription factor binding motifs potentially significant for gene regulation or protein structure. Whole-genome sequencing was performed for genomic DNA from Manych Merino rams (n = 30) on an Illumina NovaSeq 6000 platform. Variants within the MYO16 region were extracted and annotated. For each variant, ±30 bp reference and alternative sequences were scanned with FIMO using the JASPAR 2020 Vertebrates PWMs to detect allele-specific gain or loss of significant motif hits. TFLink (Mus musculus) was used to retain only TFs with MYO16 listed as a target. In the MYO16 gene region, 10,318 variants were detected. The coding region contained 54 SNPs, including 15 missense variants. In silico TFBS scanning identified 23 variants showing allele-specific gain or loss of significant motif hits, involving motifs for EBF1, CTCF, NRF1, SPI1, NFE2L2, JUN, and GFI1. We examined polymorphism in the ovine MYO16 gene region and identified candidate variants to be tested for association with productivity traits in future genotype–phenotype studies. Full article

Mycotoxins can contaminate food and raw food materials and are a threat to animal and human health. T-2 toxin is the most toxic secondary metabolite mainly produced by Fusarium species among trichothecenes. T-2 toxin exposure can induce multiple toxic effects, including hepatotoxicity, nephrotoxicity, immunotoxicity, gastrointestinal toxicity, and reproductive toxicity. Recent studies have reported that T-2 toxin can cross the blood–brain barrier and trigger neurotoxicity. In this review, we summarized the neurotoxic effects caused by T-2 toxin exposure and the underlying molecular mechanisms. Additionally, effective neuroprotective agents, potential clinical applications, and future prospects are discussed. The current studies revealed that the molecular mechanisms of T-2 toxin-induced neurotoxicity involve oxidative stress, mitochondrial dysfunction, neuroinflammation, autophagy, ferroptosis and cell apoptosis. Several signaling pathways, including NFE2L2, NRF-2, PGC-1, p53, BTG2, AKNA, MAPK, Akt, mTOR, HMGB1, HIF-1, CREB, and NF-κB, are involved. Additionally, it was reported that several antioxidants, small inhibitors and nature products, such as daucosterol, betulinic acid, AHN 1-055 hydrochloride, dimethyl fumarate and minocycline supplementations, can partly ameliorate these harmful effects. This review provides valuable insights into the underlying mechanisms of T-2 toxin-induced neurotoxicity and novel effective detoxification strategies. Full article

In recent years, insect-derived peptides have attracted attention for their potential biological activities, particularly antioxidant properties. This study assessed the antioxidant activity of two widely consumed edible insects, T. molitor and A. diaperinus larvae, using cell-free and cell-based approaches. Whole lyophilized larvae, digestion products from the oral, gastric, and intestinal phases, as well as the <3 kDa permeate fraction (D-P3) derived from the intestinal digestion phase, were evaluated using biochemical antioxidant assays. Overall, digested samples exhibited higher antioxidant capacity than their undigested counterparts. At the cellular level, treatment of LPS-stimulated, PMA-differentiated THP-1 macrophages with A. diaperinus D-P3 was associated with increased mRNA expression of genes related to antioxidant defense, including NFE2-like bZIP transcription factor 2 (NFE2L2, also known as Nrf2), glutathione-disulfide reductase (GSR), superoxide dismutase 1 (SOD1), and catalase (CAT), whereas T. molitor D-P3 preferentially modulated nuclear factor kappa B p50 subunit (NFKB1) and nuclear factor kappa B p65 subunit (RELA). Overall, these findings indicate that gastrointestinal digestion enhances the bioaccessibility of antioxidant components in both edible insect species while revealing species-specific transcriptional responses under in vitro inflammatory conditions. This multilevel assessment provides mechanistic insight into the antioxidant-related biological activity of digestion-derived insect peptides and supports their further investigation as functional ingredients in food and feed systems. Full article

A new category of polyphenolic compounds, like flavonoids, phenolic acids, phenylpropanoids, terpenoids, and others, referred to as food nutrients, may counteract the harmful effects of micro- and nanoplastics (MNPs) by enhancing cellular stress resilience response and overall human health. These compounds found in functional food help mitigate the cellular damage, inflammation, and oxidative stress caused by MNP exposure, which can contribute to pathological conditions, including diabetes. Importantly, specific food nutrients are able to activate, at the minimum dose, the nuclear factor erythroid-derived 2-like 2 (Nrf2) to prevent or block MNP-induced damage. The Nfe2l2 gene encodes the Nrf2 transcription factor, acting as a master regulator of redox homeostasis by inducing antioxidant response element (ARE)-driven resilience genes, which in turn, promote the expression of detoxification enzymes like heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1), and glutathione S-transferase (GST) to scavenge reactive oxygen species (ROS) and shield cells from environmental damage and toxicity. Deregulation of the Nfe2l2 gene due to the accumulation of MNP pollutants may exacerbate the inflammatory conditions associated with diabetes and its chronic complications by rendering cells more sensitive to oxidative stress, apoptosis, and pyroptosis. Furthermore, epigenetic modifications influence gene regulation; chromatin remodeling directly impacts DNA accessibility, allowing or limiting transcription factor access to regulate gene expression. This mechanism may also play a pivotal role in the progression of oxidative stress-related diseases, as it modulates the Nrf2 pathway and the expression levels of its target genes. In contrast to the current literature, which has only addressed the pathological mechanisms induced by MNPs, this research explores, for the first time, how food nutrients interacting with the Nfe2l2 gene can combat or reverse the toxic effects of MNPs in cells, tissues, and organs. The goal is to improve health by attenuating MNP toxicity, which is influenced by individual genetic variations and cellular stress resilience. Full article

The therapeutic potential of functional nutrients has garnered considerable attention for enhancing resilience signaling and counteracting the damage to human health caused by microplastic pollutants. The intricate interactions between microplastics (MPs) and nanoplastics (NPs) and functional nutrients, including polyphenols, flavonoids, phenylpropanoids, phenolic acids, diterpenoids, and triterpenoids, have been shown to improve blood–brain barrier (BBB) homeostasis and brain function by inhibiting oxidative stress, ferroptosis, and inflammation linked to the pathogenesis of metabolic and brain disorders. Interestingly, nutrients exhibit biphasic dose–response effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and stress-resilience proteins at minimum doses, thereby preventing or blocking MP and NP-induced damage. Notably, chronic exposure to environmental pollutants causes aberrant regulation of NFE2L2 gene and related antioxidant signaling, which can exacerbate selective susceptibility to brain insulin resistance under inflammatory conditions. This, in turn, impairs glucose metabolism and facilitates β-amyloid (Aβ) plaque synthesis leading to the onset and progression of Alzheimer’s disease (AD), also known as “Type 3 diabetes”. This pathological process triggered by oxidative stress, inflammation, and ferroptosis creates a vicious cycle that ultimately contributes to neuronal damage and loss. The review aims to investigate the therapeutic potential of functional nutrients targeting the Nrf2 pathway and stress resilience proteins to regulate epigenetic alterations, and to explore the underlying molecular mechanisms using innovative in vitro platforms for the development of promising preventive strategies and personalized nutritional interventions to attenuate oxidative stress, ferroptosis, and inflammation, with the goal of ultimately improving clinical outcomes. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) orchestrates redox balance, metabolism, and cellular stress responses, acting as both a tumor suppressor and promoter depending on the disease stage. In advanced cancers, persistent NRF2 activation—through KEAP1/NFE2L2 mutations or oxidative adaptation—drives epithelial-to-mesenchymal transition, metabolic reprogramming, and immune evasion, promoting tumor invasion (T) and metastasis (M). Recent pharmacologic efforts seek to exploit this duality. NRF2 inhibitors such as brusatol, halofuginone, and ML385 suppress NRF2 transcriptional activity or disrupt DNA binding, reducing motility, invasion, and metastatic dissemination in preclinical models. In contrast, NRF2 activators, such as bardoxolone methyl (CDDO-Me), sulforaphane, and dimethyl fumarate, exhibit chemopreventive effects by enhancing detoxification and mitigating oxidative DNA damage during early tumorigenesis. Furthermore, metabolic interventions, such as glutaminase or G6PD inhibitors, target NRF2-driven anabolic and antioxidant pathways essential for metastatic fitness. Therefore, understanding the temporal and contextual effects of NRF2 signaling is crucial for therapeutic design. The aim of this review is to examine how pharmacological modulation of NRF2 influences the invasive and metastatic dimensions of tumor progression, in addition to discussing its potential integration into TNM-based prognostic and treatment frameworks. Full article

Background/Objectives: Atrazine (ATZ) is a widely used herbicide, and most studies of its reproductive toxicity have been conducted in vivo using animal models, where ATZ disrupts redox homeostasis, leading to male reproductive dysfunction. However, its molecular mechanisms of action in human spermatogenic cells remain poorly understood. Huntington’s disease (HD), an autosomal dominant disorder caused by abnormal CAG repeat expansion in the HTT gene, exhibits heightened oxidative stress sensitivity and mitochondrial dysfunction, which may further impair reproductive function. This study investigated ATZ effects on human spermatogenesis using an in vitro spermatogenesis (IVS) model derived from human induced pluripotent stem cells (hiPSCs), focusing on Nrf2-mediated oxidative responses and apoptotic regulation during spermatogonial stem cell-like cell (SSCLC) differentiation in wild-type (WT) and HD hiPSC lines. Methods: Two WT and two HD hiPSC lines carrying 44 (HD1) and 180 (HD2) CAG repeats were treated with ATZ (0, 0.01, 1, or 10 μM) for 30 days, followed by differentiation into SSCLCs for 15 days under continuous exposure. Expression of pluripotency (OCT4, SOX2), oxidative stress (NFE2L2, SOD1, GPX1, NQO1), cell cycle (CDK1), apoptosis (BCL2, BAX, CASP3, CASP9, FAS, FASLG), and spermatogenic markers (DAZL, ZBTB16, GFRA1, PIWIL2) were assessed by immunocytochemistry and qRT-PCR. Results: Long-term ATZ exposure affected pluripotency markers in hiPSCs and SSCLC differentiation in a cell line–dependent manner. WT cells exhibited early differentiation suppression without significant apoptosis. HD1 cells were highly sensitive: low ATZ doses (0.01–1 μM) partially activated intrinsic and extrinsic apoptotic pathways, whereas high-dose ATZ (10 μM) reduced Nrf2-target and spermatogenic gene expression, strongly impairing SSCLC maturation. HD2 cells showed pronounced oxidative stress with robust Nrf2-driven antioxidant responses and BCL2 that supported differentiation at low doses. However, excessive oxidative or proliferative signaling, including CDK1 upregulation at high ATZ concentrations, disrupted redox balance and SSCLC differentiation in HD2 cells. Conclusions: ATZ exerts dose- and genotype-dependent effects on IVS through coordinated regulation of oxidative stress and apoptosis. These findings highlight the interplay between Nrf2-mediated antioxidant defenses, apoptotic signaling, and genetic background in shaping spermatogenic outcomes, providing mechanistic insight into ATZ-induced reproductive toxicity in a human-relevant in vitro spermatogenesis model. Full article

Neuronutrition to improve brain resilience to stress and human health has received considerable attention. The use of specific nutrients is effective in preventing and slowing neurodegenerative and neuropsychiatric disorders. Selective neuronutrients, including polyphenols, short-chain fatty acids (SCFAs), tryptophan, tyrosine, and sulfur metabolites, can modulate the dysregulated nuclear factor erythroid 2 (Nrf2) pathway through neuroepigenetic modifications and altered levels of neurotransmitters such as serotonin, melatonin, and dopamine. In particular, abnormal epigenetic alterations in the promoter function of the NFE2L2/Nrf2 gene may contribute to the onset and progression of various diseases by disrupting cellular homeostasis. Recent evidence has documented that polyphenols are capable of modulating Nrf2 signaling; to do this, they must reverse hypermethylation in the CpG islands of the NFE2L2 gene. This process is achieved by modifying the activity of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). Furthermore, a diverse group of polyphenolic metabolites can be identified and quantified using innovative mass spectrometry platforms in both in vitro models and human urine samples to investigate redox metabolic homeostasis under physiological and pathophysiological conditions. This review aims to deepen the current understanding of the role of nutrient-derived secondary metabolites. It highlights innovative strategies to effectively prevent, slow, or potentially reverse neuroinflammation and oxidative stress, key drivers of neuronal damage. The targeted application of these metabolites can be considered a novel, personalized neuronutritional approach to promote brain health and neuronal adaptation. Full article

Doxorubicin (Dox) is a potent anthracycline antitumor drug whose clinical utility is significantly restricted by its dose-dependent, cumulative cardiotoxicity, driven by increased oxidative stress, impaired antioxidant defenses, and apoptosis-mediated cardiomyocyte loss. Methylene blue (MB), a phenothiazine derivative with well-documented redox-modulating properties, is being explored as a viable cardioprotective agent due to its antioxidant and anti-apoptotic effects. This study evaluated the protective role of MB against Dox-induced cardiotoxicity in rats by examining its impact on oxidative stress markers (Kelch-like ECH-associated protein 1; KEAP1, nuclear factor erythroid 2-related factor 2; NRF2, Glutathione peroxidase 4; GPX-4, 8-hydroxy-2′-deoxyguanosine; 8-OHdG), neurohormonal indicators (noradrenaline), cardiac injury biomarkers (troponin I), and apoptotic mediators (p53, Caspase-3). Forty male albino rats were divided equally into four groups: control, Dox (15 mg/kg, i.p.), MB alone (4 mg/kg/day, p.o. for 7 days), and Dox plus MB. Dox administration significantly increased serum troponin I and noradrenaline levels, elevated cardiac KEAP1 and 8-OHdG, and reduced NFE2L2, NRF2, and GPX-4 expression. It also upregulated p53 and Caspase-3 and caused marked myocardial degeneration, necrosis, and inflammatory infiltration. MB co-treatment significantly reduced troponin I and noradrenaline levels, restored KEAP1/NFE2L2 (NRF2)/GPX-4 pathway balance, decreased oxidative DNA damage, and attenuated p53 and Caspase-3 activation, preserving myocardial architecture with minimal inflammatory changes. These findings demonstrate that MB confers potent cardioprotection against Dox-induced cardiac injury by enhancing antioxidant defenses, limiting oxidative DNA damage, suppressing apoptosis, and normalizing neurohormonal imbalance, suggesting its promise as an adjunctive strategy to mitigate anthracycline-associated cardiotoxicity. Full article

Ferroptosis is a distinct form of regulated cell death driven by iron-dependent lipid peroxidation participating in various diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular redox homeostasis and a key determinant of ferroptosis resistance. Nrf2 activates the expression of downstream antioxidant genes to protect cells from oxidative stress and ferroptosis. Consequently, precise regulation of Nrf2 expression is crucial. Recent studies have revealed that complex epigenetic mechanisms involving DNA methylation, histone modifications, and non-coding RNA networks regulate Nrf2 expression. DNA methylation usually suppresses while histone acetylation promotes Nrf2 expression. The influences of histone methylation on NFE2L2 are site- and methylation degree-dependent. m6A modification stabilizes NFE2L2 mRNA to promote Nrf2 expression and thereby inhibit ferroptosis. This article summarizes current understanding of the epigenetic mechanisms controlling Nrf2 expression and Nrf2-mediated ferroptosis pathways and their implications in disease models. The challenges associated with the epigenetic regulation of Nrf2 and future research directions are also discussed. A comprehensive understanding of this regulatory interplay could open new avenues for intervention in ferroptosis-related diseases by fine-tuning cellular redox balance through the epigenetic modulation of Nrf2. Full article