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Ferroptosis is a type of programmed cell death characterized by accumulation of free iron, reactive oxygen species generation and lipid peroxidation and is distinct from other types of regulated cell deaths such as apoptosis, necrosis and autophagy. Ferroptosis is distinct from other programmed cell deaths for its iron dependence and its significant role in tumor suppression. Therefore, harnessing ferroptosis may offer promising avenues for cancer therapy. In the present review, the different pathways that lead to ferroptosis, the genes and transcription factors involved in both iron and lipid metabolism, as well as the impact of small‑molecule alterations on the regulation of ferroptotic cell death, were discussed. Furthermore, the emergence of combination therapies with ferroptosis‑inducing molecules that overcome resistance to conventional chemotherapy, particularly in solid tumors, were highlighted. Show less

Ferroptosis, the non-apoptotic, iron-dependent form of cell death is an unavoidable outcome and byproduct of cellular metabolism. Reactive oxygen species generation during metabolic activities transcends to ­Fe2+-induced lipid peroxidation, leading to ferroptosis. Cancer cells being highly metabolic are more prone to ferroptosis. However, their neoplastic nature enables them to bypass ferroptosis and become ferroptosis-resistant. The capability of cancer cells to reprogram its metabolic activities is one of its finest abilities to abort oxidative damage, and hence ferroptosis. Moreover, the reprogrammed metabolism of cancer cells, also associates with the radical trapping antioxidant Show less

Abstract Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment. Show less

Ferroptosis, the non-apoptotic, iron-dependent form of cell death is an unavoidable outcome and byproduct of cellular metabolism. Reactive oxygen species generation during metabolic activities transcends to ­Fe2+-induced lipid peroxidation, leading to ferroptosis. Cancer cells being highly metabolic are more prone to ferroptosis. However, their neoplastic nature enables them to bypass ferroptosis and become ferroptosis-resistant. The capability of cancer cells to reprogram its metabolic activities is one of its finest abilities to abort oxidative damage, and hence ferroptosis. Moreover, the reprogrammed metabolism of cancer cells, also associates with the radical trapping antioxidant Show less

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. It plays a crucial role in various pathological conditions, including neurodegenerative diseases, cancer, ischemia–reperfusion injury, and organ failure. This review systematically explores the key mechanisms underlying ferroptosis, including polyunsaturated fatty acidcontaining phospholipid (PUFA-PL) peroxidation, iron metabolism, and mitochondrial dysfunction. Additionally, we summarize major endogenous ferroptosis defense systems, including the SLC7A11-glutathione (GSH)-glutathione peroxidase Show less

Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, which plays a critical role in the pathogenesis of various diseases, including ischemic tissue injury, infectious diseases, neurodegenerative disorders, and cancer. The regulatory mechanisms underlying ferroptosis involve a complex interplay of multiple subcellular organelles, orchestrating iron homeostasis, lipid metabolism, and the generation of reactive oxygen species (ROS) that drive peroxidation processes, ultimately leading to membrane damage and cell death. Numerous antioxidant systems play pivotal roles in regulating and preventing ferroptosis, among which the recently identified mitochondrial inner membrane enzyme dihydroorotate dehydrogenase (DHODH) represents a novel therapeutic target for ferroptosis intervention. This systematic review comprehensively elucidates several key cellular defense mechanisms against ferroptosis that counteract ROS-driven peroxidation and operate through distinct subcellular localizations. We particularly focus on delineating the molecular mechanisms by which DHODH regulates ferroptosis, with special emphasis on its role in suppressing mitochondrial lipid peroxidation. Furthermore, we systematically evaluate the therapeutic potential of DHODH inhibitors in oncology, virology, and immune-inflammatory disorders. By integrating ferroptosis biology with DHODH-mediated cytoprotective networks, this review aims to provide mechanistic insights and novel therapeutic strategies for cancer and oxidative stress-related disorders. Show less

Abstract Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment. Show less

Ferroptosis, a regulated form of cell death, is intricately linked to iron‑dependent lipid peroxidation. Recent evidence strongly supports the induction of ferroptosis as a promising strategy for treating cancers resistant to conventional therapies. A key player in ferroptosis regulation is ferroptosis suppressor protein 1 (FSP1), which promotes cancer cell resistance by promoting the production of the antioxidant form of coenzyme Q10. Of note, FSP1 confers resistance to ferroptosis independently of the glutathione (GSH) and glutathione peroxidase‑4 pathway. Therefore, targeting FSP1 to weaken its inhibition of ferroptosis may be a viable strategy for treating refractory cancer. This review aims to clarify the molecular mechanisms underlying ferroptosis, the specific pathway by which FSP1 suppresses ferroptosis and the effect of FSP1 inhibitors on cancer cells. Show less

Ferroptosis, a form of regulated cell death mediated by lipid peroxidation (LPO), has become the subject of intense research due to its potential therapeutic applications in cancer chemotherapy as well as its pathophysiological role in ischemic organ injury. The role of mitochondrial lipid peroxidation (LPO) in ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate (FAC) in combination with buthionine sulfoximine (BSO, an inhibitor of glutathione biosynthesis) induces mitochondrial lipid peroxidation that precedes ferroptosis in normal human fibroblasts. The mitochondrial-targeted antioxidant SkQ1 and the redox mediator methylene blue, which inhibits the production of reactive oxygen species (ROS) in complex I of the mitochondrial electron transport chain, prevent both mitochondrial lipid peroxidation and ferroptosis, but do not affect the cytosolic ROS accumulation. These data indicate that mitochondrial lipid peroxidation is required for ferroptosis induced by exogenous iron. FAC in the absence of BSO stimulates mitochondrial peroxidation without reducing cell viability. Glutathione depletion by BSO does not affect FAC-induced mitochondrial LPO but strongly stimulates the accumulation of ROS in the cytosol. These data allow us to conclude that mitochondrial LPO is not sufficient for ferroptosis and that cytosolic ROS mediates additional oxidative events that stimulate ferroptosis in conjunction with mitochondrial LPO. Show less

Ferroptosis induced by erastin (an inhibitor of cystine transport) and butionine sulfoximine (an inhibitor of glutathione biosynthesis) was prevented by the mitochondria-targeted antioxidants SkQ1 and MitoTEMPO. These effects correlate with the prevention of mitochondrial lipid peroxidation, which precedes cell death. Methylene blue, a redox agent that inhibits the production of reactive oxygen species (ROS) in complex I of the mitochondrial electron transport chain, also inhibits ferroptosis and mitochondrial lipid peroxidation. Activation of ROS production in complex I with rotenone in the presence of ferrous iron stimulates lipid peroxidation in isolated mitochondria, while ROS produced by complex III are ineffective. SkQ1 and methylene blue inhibit lipid peroxidation. We suggest that ROS formed in complex I promote mitochondrial lipid peroxidation and ferroptosis. Show less

Ferroptosis, a recently identified form of regulated cell death characterized by the irondependent 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. Show less

Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers^1-3. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H⁺ as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis^4-6. To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor⁵, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity⁷. N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy. Show less

Mechanisms of defense against ferroptosis (an iron-dependent form of cell death induced by lipid peroxidation) in cellular organelles remain poorly understood, hindering our ability to target ferroptosis in disease treatment. In this study, metabolomic analyses revealed that treatment of cancer cells with glutathione peroxidase 4 (GPX4) inhibitors results in intracellular glycerol-3-phosphate (G3P) depletion. We further showed that supplementation of cancer cells with G3P attenuates ferroptosis induced by GPX4 inhibitors in a G3P dehydrogenase 2 (GPD2)-dependent manner; GPD2 deletion sensitizes cancer cells to GPX4 inhibition-induced mitochondrial lipid peroxidation and ferroptosis, and combined deletion of GPX4 and GPD2 synergistically suppresses tumor growth by inducing ferroptosis in vivo. Mechanistically, inner mitochondrial membrane-localized GPD2 couples G3P oxidation with ubiquinone reduction to ubiquinol, which acts as a radical-trapping antioxidant to suppress ferroptosis in mitochondria. Taken together, these results reveal that GPD2 participates in ferroptosis defense in mitochondria by generating ubiquinol. Show less

Peroxidation of cardiolipin (CL) in the inner mitochondrial membrane plays a key role in the development of various pathologies and, probably, aging. The four fatty acid tails of CL are usually polyunsaturated, which makes CL particularly sensitive to peroxidation. Peroxidation of CL is involved in the initiation of apoptosis, as well as in some other important cellular signaling chains. However, the studies of CL peroxidation are strongly limited by the lack of methods for its tracing in living cells. We have synthesized a new mitochondria-targeted fluorescent probe sensitive to lipid peroxidation (dubbed MitoCLox), where the BODIPY fluorophore, carrying a diene-containing moiety (as in the C11-BODIPY (581/591) probe), is conjugated with a triphenylphosphonium cation (TPP+) via a long flexible linker that contains two amide bonds. The oxidation of MitoCLox could be measured either as a decrease of absorbance at 588 nm or as an increase of fluorescence in the ratiometric mode at 520/590 nm (emission). In CL-containing liposomes, MitoCLox oxidation was induced by cytochrome c and developed in parallel with cardiolipin oxidation. TPP+-based mitochondria-targeted antioxidant SkQ1, in its reduced form, inhibited oxidation of MitoCLox concurrently with the peroxidation of cardiolipin. Molecular dynamic simulations of MitoCLox in a cardiolipin-containing membrane showed affinity of positively charged MitoCLox to negatively charged CL molecules; the oxidizable diene moiety of MitoCLox resided on the same depth as the cardiolipin lipid peroxides. We suggest that MitoCLox could be used for monitoring CL oxidation in vivo and, owing to its flexible linker, also serve as a platform for producing peroxidation sensors with affinity to particular lipids. Show less