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Ferroptosis, a novel form of regulated cell death characterized by iron-mediated lipid peroxidation, holds immense potential in cancer therapeutics due to its role in tumor progression and resistance. This review predominantly explores the intricate relationship between ferroptosis and cholesterol metabolism pathways, mainly focusing on the cholesterol biosynthesis pathway. This review highlights the therapeutic implications of targeting cholesterol metabolism pathways for cancer treatment by delving into the mechanisms underlying ferroptosis regulation. Strategies such as inhibiting HMG-CoA reductase and suppressing squalene synthesis offer promising avenues for inducing ferroptosis in cancer cells. Moreover, insights into targeting the 7-dehydrocholesterol pathway provide novel perspectives on modulating ferroptosis susceptibility and managing ferroptosis-associated diseases. Understanding the interplay between ferroptosis and cholesterol metabolism pathways underscores the potential of lipid metabolism modulation as an innovative therapeutic approach in cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results. Abbreviation : 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green™ SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy.

The TP53 gene, encoding the p53 protein, has been a focal point of research since its 1979 discovery, playing a crucial role in tumor suppression. Ferroptosis, a distinct form of cell death characterized by lipid peroxide accumulation, has gained prominence since its recognition in 2012. Recent studies have unveiled an intriguing connection between p53 and ferroptosis, with implications for cancer therapy. Recent research underscores p53 as a novel target for cancer therapy, influencing key metabolic processes in ferroptosis. Notably, p53 represses the expression of the cystine-glutamate antiporter SLC7A11, supporting p53-mediated tumor growth suppression. Furthermore, under metabolic stress, p53 mitigates ferroptosis sensitivity, aiding cancer cells in coping and delaying cell death. This dynamic interplay between p53 and ferroptosis has far-reaching implications for various diseases, particularly cancer. This review provides a comprehensive overview of ferroptosis in cancer cells, elucidating p53's role in regulating ferroptosis, and explores the potential of targeting p53 to induce ferroptosis for cancer therapy. Understanding this complex relationship between p53 and ferroptosis offers a promising avenue for developing innovative cancer treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ferroptosis is a newly recognized form of oxidative-regulated cell death resulting from iron-mediated lipid peroxidation accumulation. Radical-trapping antioxidant systems can eliminate these oxidized lipids and prevent disrupting the integrity of cell membranes. Epigenetic modifications can regulate ferroptosis by altering gene expression or cell phenotype without permanent sequence changes. These mechanisms include DNA methylation, histone modifications, RNA modifications, and noncoding RNAs. Epigenetic alterations in cancer can control the expression of ferroptosis regulators or related pathways, leading to changes in cell sensitivity to ferroptosis inducers or cancer progression. Epigenetic alterations in cancer are influenced by a wide range of cancer hallmarks, contributing to therapeutic resistance. Targeting epigenetic alterations is a promising approach to overcoming cancer resilience. However, the exact mechanisms involved in different types of cancer remain unresolved. Discovering more ferroptosis-associated epigenetic targets and interventions can help overcome current barriers in anticancer therapy. Many papers on epigenetic modifications of ferroptosis have been continuously published, making it essential to summarize the current state-of-the-art in the epigenetic regulation of ferroptosis in human cancer., (© 2023. Springer Nature Switzerland AG.)

Ferroptosis is a newly discovered form of programmed cell death caused by redox-active iron-mediated lipid peroxidation. Ferroptosis exhibits a unique morphological phenotype resulting from oxidative damage to membrane lipids. Ferroptosis induction has been shown to be effective in treating human cancers that rely on lipid peroxidation repair pathways. Nuclear factor erythroid 2-related factor 2 (Nrf2) can control the regulatory pathways of ferroptosis, which involve genes associated with glutathione biosynthesis, antioxidant responses, and lipid and iron metabolism. Resistant cancer cells often utilize Nrf2 stabilization by Keap1 inactivation or other somatic alterations in the genes from the Nrf2 pathway, which can confer resistance to ferroptosis induction and other therapies. However, pharmacological inactivation of the Nrf2 pathway can sensitize cancer cells to ferroptosis induction. Inducing lipid peroxidation and ferroptosis through regulating the Nrf2 pathway is a promising strategy for enhancing the anticancer effects of chemotherapy and radiation therapy in therapy-resistant human cancers. Despite promising preliminary studies, clinical trials in human cancer therapy have not yet been realized. A deeper understanding of their exact processes and efficacies in various cancers remains unsolved. Therefore, this article aims to summarize the regulatory mechanisms of ferroptosis, their modulation by Nrf2, and the potential of targeting Nrf2 for ferroptosis-based cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ferroptosis is a recently identified type of regulated cell death characterized by lipid peroxidation and redox-active iron accumulation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of genes involved in glutathione biosynthesis, antioxidant responses, lipid metabolism, and iron metabolism, contributing to the evasion of ferroptosis. Inhibiting the Nrf2 pathway has been shown to sensitize cancer cells to ferroptosis. In head and neck cancer cells, we found that activation of the Nrf2-antioxidant responsive element pathway leads to ferroptosis resistance, and inhibiting this pathway reverses ferroptosis evasion. Our study suggests that modulating the Nrf2 pathway could be a promising strategy to overcome resistance in cancer therapy for head and neck cancer. Further research is required to investigate the potential of ferroptosis induction in therapy-resistant head and neck cancer. Targeting Nrf2 through ferroptosis-based cancer therapy may be a novel and effective approach to reverse the resistance of head and neck cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Iron is a mineral micronutrient essential for survival and vital functions in many biological processes in living organisms. Iron plays a crucial role as a cofactor of iron-sulfur clusters in energy metabolism and biosynthesis by binding with enzymes and transferring electrons to targets. Iron can also impair cellular functions by damaging organelles and nucleic acids by producing free radicals from redox cycling. Iron-catalyzed reaction products can induce active-site mutations in tumorigenesis and cancer progression. However, the boosted pro-oxidant iron form may contribute to cytotoxicity by increasing soluble radicals and highly reactive oxygen species via the Fenton reaction. An increased redox-active labile iron pool is required for tumor growth and metastasis, but the increased cytotoxic lipid radicals also lead to regulated cell death, such as ferroptosis. Therefore, this may be a major target for selectively killing cancer cells. This review intends to understand altered iron metabolism in cancers and discuss iron-related molecular regulators highly associated with iron-induced cytotoxic radical production and ferroptosis induction, focusing on head and neck cancer., (© 2023. Springer Nature Switzerland AG.)

Divalent metal transporter 1 (DMT1) inhibitors can selectively kill iron-addicted cancer stem cells by causing lysosomal iron overload, but their role in head and neck cancer (HNC) is unknown. We examined the role of DMT1 inhibition or salinomycin in promoting ferroptosis by lysosomal iron targeting in HNC cells. RNA interference was performed by transfection of siRNA targeting DMT1 or scrambled control siRNA in HNC cell lines. Cell death and viability, lipid peroxidation, iron contents, and molecular expression were compared between the DMT1 silencing or salinomycin group and the control. DMT1 silencing markedly accelerated cell death induced by the ferroptosis inducers. DMT1 silencing marked increases in the labile iron pool, intracellular ferrous and total iron contents, and lipid peroxidation. DMT1 silencing revealed molecular changes in iron starvation response, resulting in increases in TFRC, and decreases in FTH1. Salinomycin treatment also showed similar results to the above DMT1 silencing. DMT1 silencing or salinomycin can promote ferroptosis in HNC cells, suggesting a novel strategy for killing iron-avid cancer cells., (© 2023. The Author(s) under exclusive licence to Japan Human Cell Society.)

Cancers polarized to a mesenchymal or poorly differentiated state can often evade cell death induced by conventional therapies. The epithelial-mesenchymal transition is involved in lipid metabolism and increases polyunsaturated fatty acid levels in cancer cells, contributing to chemo- and radio-resistance. Altered metabolism in cancer enables invasion and metastasis but is prone to lipid peroxidation under oxidative stress. Cancers with mesenchymal rather than epithelial signatures are highly vulnerable to ferroptosis. Therapy-resistant persister cancer cells show a high mesenchymal cell state and dependence on the lipid peroxidase pathway, which can respond more sensitively to ferroptosis inducers. Cancer cells may survive under specific metabolic and oxidative stress conditions, and targeting this unique defense system can selectively kill only cancer cells. Therefore, this article summarizes the core regulatory mechanisms of ferroptosis in cancer, the relationship between ferroptosis and epithelial-mesenchymal plasticity, and the implications of epithelial-mesenchymal transition for ferroptosis-based cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cancer metabolic alterations have been emphasized to protect cancer cells from cell death. The metabolic reprogramming toward a mesenchymal state makes cancer cells resistant to therapy but vulnerable to ferroptosis induction. Ferroptosis is a new form of regulated cell death based on the iron-dependent accumulation of excessive lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the core regulator of ferroptosis by detoxifying cellular lipid peroxidation using glutathione as a cofactor. GPX4 synthesis requires selenium incorporation into the selenoprotein through isopentenylation and selenocysteine tRNA maturation. GPX4 synthesis and expression can be regulated by multiple levels of its transcription, translation, posttranslational modifications, and epigenetic modifications. Targeting GPX4 in cancer may be a promising strategy for effectively inducing ferroptosis and killing therapy-resistant cancer. Several pharmacological therapeutics targeting GPX4 have been developed constantly to activate ferroptosis induction in cancer. The potential therapeutic index of GPX4 inhibitors remains to be tested with thorough examinations of their safety and adverse effects in vivo and clinical trials. Many papers have been published continuously in recent years, requiring state-of-the-art updates in targeting GPX4 in cancer. Herein, we summarize targeting the GPX4 pathway in human cancer, which leads to implications of ferroptosis induction for tackling cancer resilience., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cancer often perturbs lipid metabolism, which leads to the alteration of metabolism intermediates, contributing to their deregulated growth and metastasis. Alteration of lipid metabolism shifting to contain more polyunsaturated fatty acids (PUFAs) in membrane phospholipids (PLs) also leads to cancer therapy resistance. High amounts of PL-PUFAs render cancer cells more vulnerable to lipid peroxidation (LPO), predisposing them towards ferroptosis, a new form of iron-dependent oxidative regulated cell death. The commitment of cancer undergoing ferroptotic cell death depends on the adaptive lipidome remodeling, LPO patterns, and LPO scavenging ability in heterogeneous cancer cells. Ferroptosis is receiving attention in cancer research as treating cancers, altering membrane lipid homeostasis, and refractory from conventional therapies. Therefore, a better understanding of the molecular underpinning of lipid metabolism alterations may provide new opportunities for solving cancer resistance. This review intends to understand altered lipid metabolism in cancers and discuss lipid composition and metabolic processes associated with ferroptosis induction in cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ferroptosis is a newly regulated cell death induced by the accumulation of iron-mediated lipid peroxidation. The alteration of cancer metabolism may contribute to proliferation, metastasis, and treatment resistance in human cancers, implicating the sensitivity to ferroptosis induction. Altered metabolism in cancer cells regulates oxidative stresses and changes metabolism intermediates, contributing to their deregulated growth and proliferation. Cancer metabolic changes toward the elevation of cellular free iron and polyunsaturated fatty acids sensitize cancer cells to lipid peroxidation toxicity tightly linked to ferroptosis. The altered metabolism in cancers can be served as a promising target to reverse cancer therapeutic resistance by ferroptosis induction to selectively kill cancer cells while sparing normal cells. The role of mitochondria and lipid metabolism in inducing ferroptosis in head and neck cancer (HNC) has been elucidated in previous studies. Ferroptosis is receiving attention in cancer research as treating cancers altering cellular metabolism and refractory from conventional therapies. More in-depth studies are needed to develop highly therapeutic drugs and practical methods to induce ferroptosis in diverse cancer cells and tumor microenvironments effectively. Therefore, this review intends to understand the altered metabolism and find new therapeutic possibilities using ferroptosis in HNC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Most head and neck cancers (HNCs) originate from mucosal epithelial cells and show epithelial traits. It often changes to a mesenchymal or poorly differentiated state as cancer progresses, leading to invasion, metastasis, and resistance to treatment. The loss of epithelial traits by the epithelial-mesenchymal transition may render resilient cancers vulnerable to a novel non-apoptotic regulated cell death ferroptosis by the iron-dependent accumulation of excessive lipid peroxidation. By regulating mitochondrial or iron metabolism, intracellular ferrous iron and lipid peroxidation accumulation can be boosted, making resistant cancer cells more susceptible to ferroptosis. This article discusses the potential effect of ferroptosis induction as a novel treatment for resilient HNCs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A cytosolic iron chaperone poly(rC)-binding protein 1 (PCBP1) is a multifunctional RNA-binding protein involving gene transcription, RNA regulation, and iron loading to ferritins. PCBP1 is also known to repress autophagy, but the role of PCBP1 in ferritinophagy and ferroptosis remains unrevealed. Therefore, we examined the role of PCBP1 in ferritinophagy-mediated ferroptosis in head and neck cancer (HNC) cells. The effects of system xc - cystine/glutamate antiporter (xCT) inhibitors and PCBP1 gene silencing/overexpression were tested on HNC cell lines and mouse tumor xenograft models. These effects were analyzed by assessing cell viability and death, lipid reactive oxygen species and iron production, lipid, malondialdehyde, mRNA/protein expression, and autophagy flux assays. Interaction between PCBP1 and BECN1 mRNA was also examined by luciferase and RNA-protein pull-down assays. PCBP1 gene silencing increased autophagosome generation and autophagic flux. Conversely, PCBP1 upregulation inhibited autophagy activation via direct binding to the CU-rich elements on the 3'-untranslated region (3'-UTR) of BECN1 mRNA. The internal deletion or mutation of the 3'-UTR F2 region recovered BECN1 mRNA stability repressed by PCBP1, resulting in enhanced ferritinophagy-mediated ferroptosis. Besides, PCBP1 knockdown promoted polyunsaturated fatty acid peroxidation by increasing ALOX15 expression. Further, excess iron accumulation caused mitochondrial dysfunction in PCBP1-suppressed cells. A ferroptosis inducer sulfasalazine significantly suppressed tumor growth in mice with the transplantation of PCBP1-silenced HNC. Our data suggest that the dual functions of PCBP1 repressing BECN1 and ALOX15 mRNAs contribute to attenuating cancer susceptibility to ferroptosis inducers., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Progesterone receptor membrane component 1 (PGRMC1) is a heme-binding protein inducing dimerization with cytochrome P450, which mediates chemoresistance. Increased PGRMC1 expression is found in multiple types of resistant cancers, but the role of PGRMC1 in the ferroptosis of cancer cells remains unrevealed. Therefore, we examined the role of PGRMC1 in promoting ferroptosis in paclitaxel-tolerant persister cancer cells (PCC)., Methods: The effects of ferroptosis inducers and PGRMC1 gene silencing/overexpression were tested on head and neck cancer (HNC) cell lines and mouse tumor xenograft models. The results were analyzed about cell viability, death, lipid ROS and iron production, mRNA/protein expression and interaction, and lipid assays., Results: PCC had more free fatty acids, lipid droplets, and fatty acid oxidation (FAO) than their parental cells. PCC was highly sensitive to inhibitors of system xc - cystine/glutamate antiporter (xCT), such as erastin, sulfasalazine, and cyst(e)ine deprivation, but less sensitive to (1S,3R)-RSL3. PGRMC1 silencing in PCC reduced ferroptosis sensitivity by xCT inhibitors, and PGRMC1 overexpression in parental cells increased ferroptosis by xCT inhibitors. Lipid droplets were degraded along with autophagy induction and autophagosome formation by erastin treatment in PCC. Lipophagy was accompanied by increased tubulin detyrosination, which was increased by SIRT1 activation but decreased by SIRT1 inhibition. FAO and lipophagy were also promoted by the interaction between lipid droplets and mitochondria., Conclusion: PGRMC1 expression increased FAO and ferroptosis sensitivity from in vivo mice experiments. Our data suggest that PGRMC1 promotes ferroptosis by xCT inhibition in PCC., (© 2021. The Author(s).)

Cancer cells evolve to survive as 'persister cells' resistant to various chemotherapeutic agents. Persister cancer cells retain mesenchymal traits that are vulnerable to ferroptosis by iron-dependent accumulation of lethal lipid peroxidation. Regulation of the KDM5A-MPC1 axis might shift cancer cells to have mesenchymal traits via epithelial-mesenchymal transition process. Therefore, we examined the therapeutic potentiality of KDM5A-MPC1 axis regulation in promoting ferroptosis in erlotinib-tolerant persister head and neck cancer cells (erPCC). ErPCC acquired mesenchymal traits and disabled antioxidant program that were more vulnerable to ferroptosis inducers of RSL3, ML210, sulfasalazine, and erastin. GPX4 and xCT suppression caused increased sensitivity to ferroptosis in vivo models of GPX4 genetic silencing. KDM5A expression increased and MPC1 expression decreased in erPCC. KDM5A inhibition increased MPC1 expression and decreased sensitivity to ferroptosis inducers in erPCC. MPC1 suppression increased vulnerability to ferroptosis in vitro and in vivo by retaining mesenchymal traits and glutaminolysis. Low expression of MPC1 was associated with low overall survival from the TCGA data. Our data suggest that regulation of the KDM5A-MPC1 axis contributes to promoting cancer ferroptosis susceptibility., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ferroptosis is a newly defined form of cell death induced by iron-dependent accumulation of lethal lipid peroxidation. Ferroptosis represent a therapeutic strategy to suppress therapy-resistant cancer cells with more property of epithelial-mesenchymal transition (EMT). However, epigenetic reprogramming of EMT has been rarely studied in the context of ferroptosis susceptibility. Therefore, we examined the therapeutic potentiality of EMT epigenetic reprogramming in promoting ferroptosis in head and neck cancer (HNC) cells. The effects of ferroptosis inducers and EMT inhibition or induction were tested in HNC cell lines and mouse tumor xenograft models. These effects were analyzed concerning cell viability and death, lipid reactive oxygen species and iron production, labile iron pool, glutathione contents, NAD/NADH levels, and mRNA/protein expression. Cell density and the expression levels of E-cadherin, vimentin, and ZEB1 were associated with the different susceptibility to ferroptosis inducers. CDH1 silencing or ZEB1 overexpression increased the susceptibility to ferroptosis, whereas CDH overexpression or ZEB1 silencing decreased the susceptibility, in vitro and in vivo. Histone deacetylase SIRT1 gene silencing or pharmacological inhibition by EX-527 suppressed EMT and consequently decreased ferroptosis, whereas SIRT inducers, resveratrol and SRT1720, increased ferroptosis. MiR-200 family inhibitors induced EMT and increased ferroptosis susceptibility. In HNC cells with low expression of E-cadherin, the treatment of 5-azacitidine diminished the hypermethylation of CDH1, resulting in increased E-cadherin expression and decreased ferroptosis susceptibility. Our data suggest that epigenetic reprogramming of EMT contributes to promoting ferroptosis in HNC cells., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Rationale: Loss of iron-sulfur cluster function predisposes cancer cells to ferroptosis by upregulating iron-starvation response, but the role of glutaredoxin 5 (GLRX5) silencing in ferroptosis remains unknown. We examined the role of GLRX5 functional loss in promoting ferroptosis in cisplatin-resistant head and neck cancer (HNC) cells. Methods: The effects of sulfasalazine treatment and GLRX5 gene silencing were tested on HNC cell lines and mouse tumor xenograft models. These effects were analyzed concerning cell viability and death, lipid reactive oxygen species (ROS) and mitochondrial iron production, labile iron pool, mRNA/protein expression, and malondialdehyde assays. Results: Cyst(e)ine deprivation, erastin, or sulfasalazine induced ferroptosis in HNC cells, which was relatively less sensitive in cisplatin-resistant HNC cells. Sulfasalazine or cyst(e)ine deprivation-induced ferroptosis resulted from increased lipid peroxidation and intracellular free iron, which were significantly promoted by short-interfering RNA or short hairpin RNA (shRNA) targeting GLRX5 ( P <0.05). GLRX5 silencing activated iron-starvation response and boosted up intracellular free iron through the iron-responsive element-binding activity of increased iron regulatory protein (increased transferrin receptor and decreased ferritin). These effects were rescued by resistant GLRX5 cDNA but not by catalytically inactive mutant GLRX5 K101Q. The same results were noted in an in vivo mouse model transplanted with vector or shGLRX5-transduced HNC cells and treated with sulfasalazine. Conclusion: Our data suggest that inhibition of GLRX5 predisposes therapy-resistant HNC cells to ferroptosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Ferroptosis, a recently identified form of regulated cell death characterized by the iron-dependent accumulation of lethal lipid peroxidation, has gained increasing attention in cancer therapy. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone oxidoreductase that reduces ubiquinone to ubiquinol, has emerged as a critical player in the regulation of ferroptosis. FSP1 operates independently of the canonical system xc–/glutathione peroxidase 4 pathway, making it a promising target for inducing ferroptosis in cancer cells and overcoming ferroptosis resistance. This review provides a comprehensive overview of FSP1 and ferroptosis, emphasizing the importance of FSP1 modulation and its potential as a therapeutic target in cancer treatment. We also discuss recent progress in developing FSP1 inhibitors and their implications for cancer therapy. Despite the challenges associated with targeting FSP1, advances in this field may provide a strong foundation for developing innovative and effective treatments for cancer and other diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Iron-sulfur clusters (ISCs) play a crucial role in cancer cell survival and growth, and their dysregulation is associated with the development and progression of cancer. This review highlights the link between ISC metabolism and ferroptosis, a new form of regulated cell death induced by iron-dependent accumulation of lethal lipid peroxidation. The review summarizes the current knowledge on the mechanisms of ISC biogenesis, the role of ISC modulation in ferroptosis, and the potential of targeting ISCs for cancer therapy. The review provides insight into new therapeutic strategies for cancer treatment based on regulating ISC metabolism. Iron dysregulation is a hallmark of cancer, characterized by an overexpression of genes involved in iron metabolism and iron-sulfur cluster (ISC) biogenesis. Dysregulated iron homeostasis increases intracellular labile iron, which may lead to the formation of excess cytotoxic radicals and make it vulnerable to various types of regulated cell death, including ferroptosis. The inhibition of ISC synthesis triggers the iron starvation response, increasing lipid peroxidation and ferroptosis in cancer cells treated with oxidative stress-inducing agents. Various methods, such as redox operations, iron chelation, and iron replacement with redox-inert metals, can destabilize or limit ISC formation and function, providing potential therapeutic strategies for cancer treatment. Targeting ISCs to induce ferroptosis represents a promising approach in cancer therapy. This review summarizes the state-of-the-art overview of iron metabolism and ferroptosis in cancer cells, the role of ISC modulation in ferroptosis, and the potential of targeting ISCs for ferroptosis induction in cancer therapy. Further research is necessary to develop and validate these strategies in clinical trials for various cancers, which may ultimately lead to the development of novel and effective treatments for cancer patients. [ABSTRACT FROM AUTHOR]

SLC7A11 is a cell transmembrane protein composing the light chain of system xc−, transporting extracellular cystine into cells for cysteine production and GSH biosynthesis. SLC7A11 is a critical gateway for redox homeostasis by maintaining the cellular levels of GSH that counter cellular oxidative stress and suppress ferroptosis. SLC7A11 is overexpressed in various human cancers and regulates tumor development, proliferation, metastasis, microenvironment, and treatment resistance. Upregulation of SLC7A11 in cancers is needed to adapt to high oxidative stress microenvironments and maintain cellular redox homeostasis. High basal ROS levels and SLC7A11 dependences in cancer cells render them vulnerable to further oxidative stress. Therefore, cyst(e)ine depletion may be an effective new strategy for cancer treatment. However, the effectiveness of the SLC7A11 inhibitors or cyst(e)inase has been established in many preclinical studies but has not reached the stage of clinical trials for cancer patients. A better understanding of cysteine and SLC7A11 functions regulating and interacting with redox-active proteins and their substrates could be a promising strategy for cancer treatment. Therefore, this review intends to understand the role of cysteine in antioxidant and redox signaling, the regulators of cysteine bioavailability in cancer, the role of SLC7A11 linking cysteine redox signaling in cancer metabolism and targeting SLC7A11 for novel cancer therapeutics. [ABSTRACT FROM AUTHOR]

The diverse functions of ferroptosis suppressor protein 1 (FSP1/AIFM2) in cancer have positioned it as a promising therapeutic target across various malignancies, including head and neck cancer (HNC). Initially characterized as a potential tumor suppressor due to its involvement in apoptosis and ferroptosis, recent studies have revealed its complex role in tumor growth, metabolism, and therapy resistance. Pharmacological inhibition of FSP1 shows potential in sensitizing cancer cells to ferroptosis and overcoming resistance to conventional therapies, offering new avenues for precision medicine approaches. Identifying novel FSP1 inhibitors and their synergistic effects with existing therapies presents exciting opportunities for therapeutic development. However, translating preclinical findings into clinical practice requires the refinement of FSP1 inhibitors, robust biomarkers for patient stratification, and further investigations into the molecular mechanisms underlying FSP1-mediated therapy resistance. Integrating FSP1-targeted therapies into comprehensive treatment regimens holds promise for improving outcomes in cancer patients and advancing the field of precision oncology. [Display omitted] • FSP1/AIFM2: Vital in cancer, influencing apoptosis, metabolism, and therapy resistance. • FSP1 inhibition: Key strategy against cancer resistance via ferroptosis induction and targeted therapy. • Novel FSP1 inhibitors: iFSP1, FSEN1, and icFSP1 offer potent anti-cancer effects, synergizing with existing treatments. • Precision oncology: FSP1 targeting aids in precise cancer patient classification, guiding combined therapies. • Future directions: Unveiling FSP1's role, optimizing treatments for enhanced efficacy and outcomes in cancers. [ABSTRACT FROM AUTHOR]

Inhibition of key molecules related to ferroptosis, cystine/glutamate antiporter and glutathione peroxidase, may induce eradication of chemotherapy/radiotherapy-resistant cancer cells. The present study investigated whether ferroptosis could overcome head and neck cancer (HNC) resistance to cisplatin treatment. Three cisplatin-resistant HNC cell lines (AMC-HN3R, -HN4R, and -HN9R) and their parental lines were used. The effects of cystine and glutamate alteration and pharmacological and genetic inhibition of cystine/glutamate antiporter were assessed by measuring viability, death, reactive oxygen species production, protein expression, and preclinical mouse tumor xenograft models. Conditioned media with no cystine or glutamine excess induced ferroptosis of both cisplatin-sensitive and -resistant HNC cells without any apparent changes to necrosis and apoptosis markers. The cystine/glutamate antiporter inhibitors erastin and sulfasalazine inhibited HNC cell growth and accumulated lipid reactive oxygen species, thereby inducing ferroptosis. Genetic silencing of cystine/glutamate antiporter with siRNA or shRNA treatment also induced effective ferroptotic cell death of resistant HNC cells and enhanced the cisplatin cytotoxicity of resistant HNC cells. Pharmacological and genetic inhibition of cystine/glutamate antiporter significantly sensitized resistant HNC cells to cisplatin in vitro and in vivo. Pharmacological and genetic inhibition of cystine/glutamate antiporter overcomes the cisplatin resistance of HNC cells by inducing ferroptosis. [ABSTRACT FROM AUTHOR]

Abstract Glutathione peroxidase 4 (GPX4) is a regulator of ferroptosis (iron-dependent, non-apoptotic cell death); its inhibition can render therapy-resistant cancer cells susceptible to ferroptosis. However, some cancer cells develop mechanisms protective against ferroptosis; understanding these mechanisms could help overcome chemoresistance. In this study, we investigated the molecular mechanisms underlying resistance to ferroptosis induced by GPX4 inhibition in head and neck cancer (HNC). The effects of two GPX4 inhibitors, (1 S , 3 R)-RSL3 and ML-162, and of trigonelline were tested in HNC cell lines, including cisplatin-resistant (HN3R) and acquired RSL3-resistant (HN3-rslR) cells. The effects of the inhibitors and trigonelline, as well as of inhibition of the p62, Keap1, or Nrf2 genes, were assessed by cell viability, cell death, lipid ROS production, and protein expression, and in mouse tumor xenograft models. Treatment with RSL3 or ML-162 induced the ferroptosis of HNC cells to varying degrees. RSL3 or ML-162 treatment increased the expression of p62 and Nrf2 in chemoresistant HN3R and HN3-rslR cells, inactivated Keap1, and increased expression of the phospho-PERK–ATF4–SESN2 pathway. Transcriptional activation of Nrf2 was associated with resistance to ferroptosis. Overexpression of Nrf2 by inhibiting Keap1 or Nrf2 gene transfection rendered chemosensitive HN3 cells resistant to RSL3. However, Nrf2 inhibition or p62 silencing sensitized HN3R cells to RSL3. Trigonelline sensitized chemoresistant HNC cells to RSL3 treatment in a mouse model transplanted with HN3R. Thus, activation of the Nrf2–ARE pathway contributed to the resistance of HNC cells to GPX4 inhibition, and inhibition of this pathway reversed the resistance to ferroptosis in HNC. Graphical abstract A proposed model of Nrf2-induced resistance to GPX4 inhibition-induced ferroptosis in cancer cells. The GPX4 inhibitors RSL3 and ML-162 induce endoplasmic reticulum stress and subsequently p62 expression via the PERK–ATF4–SESN2 pathways. Nrf2 is activated by p62–Keap1 interaction and antioxidant response elements (ARE) related to iron and antioxidant systems is increased, resulting in a decreased labile iron pool, thus contributing to the resistance to ferroptosis. fx1 Highlights • RSL3 and ML-162 inhibited GPX4, inducing the ferroptotic death of head and neck cancer (HNC) cells to varying degrees. • Resistance to GPX4 inhibition is related to the increased expression of p62. • The p62–Keap1–Nrf2 antioxidant system is also involved in the RSL3 resistance mechanism. • Nrf2 inhibition sensitized chemoresistant HNC cells to RSL3 treatment. • Trigonelline reversed RSL3-induced resistance to ferroptosis in HNC via inhibition of the Nrf2 system, both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Sulfasalazine has been repurposed to induce ferroptotic cancer cell death via inhibition of xc--cystine/glutamate antiporter (xCT). However, cancer cells are capable of developing mechanisms to evade cell death. Therefore, we sought to determine the molecular mechanisms underlying resistance to sulfasalazine-induced ferroptosis in head and neck cancer (HNC). The effects of sulfasalazine and pioglitazone were tested in various HNC cell lines. The effects of these drugs and inhibition and overexpression of CISD2 gene were determined by evaluating viability, cell death, lipid ROS production, mitochondrial iron, and mouse tumor xenograft models. SAS induced ferroptotic cell death in HNC at different levels. CISD2 expression showed an association between its expression and ferroptosis resistance. CISD2 overexpression conferred resistance to ferroptosis by sulfasalazine. Silencing CISD2 gene rendered resistant HNC cells susceptible to sulfasalazine-induced ferroptosis, with increased levels of lipid ROS and mitochondrial ferrous iron. Pioglitazone induced over-accumulation of mitochondrial iron and ROS and sensitized resistant HNC cells to sulfasalazine treatment in vitro and in a mouse tumor-xenograft model. CISD2 inhibition overcomes HNC resistance to ferroptotic cell death induced by sulfasalazine via increased accumulation of mitochondrial ferrous iron and lipid ROS. [ABSTRACT FROM AUTHOR]