Ovarian cancer remains the most lethal gynaecological malignancy, due to late diagnosis, extensive peritoneal dissemination, and the common emergence of therapy resistance. While intrinsic genomic instability and DNA repair defects have long been considered the main biological events underlying ovarian cancer pathogenesis, it is now evident that disease progression is critically shaped by the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) constitute the main immune population in both solid lesions and malignant ascites, orchestrating tumor growth, metastatic dissemination, immune evasion, and chemoresistance. In parallel, ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death, has emerged as a therapeutic vulnerability in ovarian cancer, particularly in platinum- and Poly (ADP-ribose) polymerase (PARP) inhibitor-resistant disease. TAMs and ferroptosis engage in a bidirectional and context-dependent crosstalk: TAMs iron handling, redox activity, and polarization states modulate ferroptotic sensitivity of ovarian cancer cells, while ferroptotic stress reshapes TAMs phenotype, cytokine release, and immunosuppressive capacity. In this review, we reframe ovarian cancer as an immune-metabolic disease in which ferroptosis and TAM biology form a tightly coupled regulatory axis. We synthesize current mechanistic insights and propose that effective therapeutic ferroptosis induction requires concurrent modulation of TAMs plasticity.

Ferroptosis, a regulated cell death modality, driven by iron-dependent lipid peroxidation, is intrinsically coupled with mitochondrial metabolic turbulence and redox dysregulation. While the mitochondrial sirtuin Sirtuin 3 (SIRT3) is canonically viewed as a master regulator of energy homeostasis, its defensive repertoire against ferroptosis extends far beyond the simplistic activation of antioxidant enzymes. In this review, we synthesize emerging evidence to construct an integrated “metabolic-structural” defense model orchestrated by SIRT3. We first delineate how SIRT3 functions as a metabolic rheostat, rewiring tricarboxylic acid (TCA) cycle flux via the deacetylation of isocitrate dehydrogenase 2 (IDH2) to sustain the nicotinamide adenine dinucleotide phosphate (NADPH)/glutathione (GSH) reservoir. Breaking away from the classical enzymatic paradigm, we highlight a novel non-enzymatic substrate regulatory mechanism where SIRT3 stabilizes the glutamate transporter SLC25A22 through specific deacetylation-ubiquitination crosstalk, thereby limiting ferroptotic susceptibility. Furthermore, we expand the SIRT3 signaling landscape by proposing a “SIRT3-nuclear factor erythroid 2-related factor 2 (Nrf2) deacetylation axis” that bridges mitochondrial stress signals to nuclear transcriptional defense, and by detailing its control over iron entry via the iron regulatory protein 1 (IRP1)-transferrin receptor 1 (TfR1) pathway. At the organelle level, we examine how SIRT3 remodels mitochondrial dynamics, upregulating optic atrophy-associated protein 1 (OPA1) while suppressing dynamin-related protein 1 (DRP1), to construct a “fusion network barrier” that dilutes ROS toxicity. We also posit a critical hypothesis: SIRT3 safeguards the integrity of mitochondria-associated endoplasmic reticulum membranes, preventing structural decoupling and calcium overload that triggers ferroptotic sensitization. Finally, we reconcile the context-dependent duality of SIRT3 in cancer and degenerative diseases, outlining future therapeutic strategies that leverage these multidimensional vulnerabilities.

Background: Glioblastoma multiforme (GBM) progression relies on active dialog between tumor cells and infiltrating immune cells, mainly including macrophages. Macrophages are closely linked to iron handling and reactive oxygen species (ROS) regulation, suggesting that ferroptosis may play a pivotal role in macrophage behavior.

Methods: Bulk RNA-seq GBM datasets, The Cancer Genome Atlas (TCGA)-GBM and gene set enrichment 4412 (GSE4412) were used to quantify immune infiltration (xCell), identify differentially expressed genes (limma), and extract ferroptosis-related markers (FerrDb V2). Ferroptosis-associated transcriptional programs were visualized using the ferroviz R package. Single-cell RNA-sequencing GBM datasets (GSE189650) were processed to characterize ferroptosis-related signatures and explore the dynamic regulation of ferroptosis-related genes in M2 tumor-associated macrophages (M2-TAMs). Deep learning neural networks were trained to predict recurrence based on ferroptosis hallmarks.

Results: High M2-TAM infiltration in poor-prognosis tumors was associated with a deregulated ferroptosis program defined by nine markers, tumor necrosis factor alpha-induced protein 3 (TNFAIP3), arachidonate lipoxygenase 5 (ALOX5), perilipin 2 (PLIN2), spermidine/spermine-N1-acetyltransferase 1(SAT1), ferritin light chain (FTL), cathepsin B (CTSB), poly (ADP-ribose) polymerase 8 (PARP8), heme oxygenase-1 (HMOX1), autophagy-related 7 (ATG7), validated at single-cell resolution and enriched in CD16+/CD163+ myeloid cells. A ferroptosis score independently predicted M2 infiltration in a clinicobiological multivariable model. Deep learning analyses revealed opposite regulation of TNFAIP3 (repressed ferroptosis driver) and FTL (upregulated ferroptosis suppressor) during recurrence, indicating impaired ferroptosis in M2-TAMs during disease progression. TNFAIP3 expression in primary tumors aligned with a pro-inflammatory signature, whereas FTL expression in recurrent tumors correlated with an invasive program involving apolipoprotein E (APO-E), serpin family E member 1 (SERPINE1), thioredoxin-interacting protein (TXNIP), glycoprotein non‑metastatic melanoma protein B (GPNMB), cystatin C (CST3), dihydrofolate reductase (DHFR), β2-microglobulin (B2M), and nuclear protein-1 (NUPR1).

Conclusion: Glioblastoma-associated macrophages display defective ferroptosis program in aggressive and recurrent tumors, linking reduced inflammatory activity to enhanced invasiveness. Restoring ferroptosis activity in these immune cells may represent a promising therapeutic strategy.

Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute respiratory failure characterized by diffuse lung inflammation and edema. Despite increased understanding of the molecular biology underlying ARDS, the complex pathogenesis still limits the development of targeted pharmacologic therapies. Cell death plays a vital role in defending against pathogen infections and triggering tissue inflammation, which can damage the alveolar-capillary barrier and ultimately lead to the development of ARDS. Thus, targeting various cell death pathways may be an attractive entry point for therapeutic intervention in ARDS. Intriguingly, recent genetic and biochemical studies have emphasized the importance of revealing the crosstalk among various cell death pathways and indicated that this connectivity exhibits a considerable degree of plasticity in the molecular regulation of potential therapeutic targets in ARDS. In this review, we summarize the mechanisms of the different types of regulated cell death (RCD) and describe the physiological and pathological processes that contribute to ARDS pathogenesis. We also discuss the emerging crosstalk among various RCD modalities, and highlight that targeting cell death pathways is an effective therapeutic strategy for ARDS.

Metabolic reprogramming fundamentally drives cancer progression, with aberrant amino acid metabolism serving as a critical nexus for maintaining redox homeostasis and dictating cell fate. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, is closely related to intracellular amino acid metabolic networks. Here, we systematically delineate how key amino acids function as multi-dimensional regulatory nodes that orchestrate tumor cell susceptibility to ferroptosis. We provide a focused analysis of the context-dependent mechanisms through which these metabolic pathways rewire cellular redox capacity, modulate central anti-ferroptotic defense nodes (e.g., GPX4), and reshape the tumor microenvironment. Finally, we highlight the profound metabolic plasticity and spatiotemporal heterogeneity of these networks, exposing the intrinsic vulnerabilities within the amino acid-ferroptosis axis that drive drug resistance and tumor evolution.

Iron is essential for cellular metabolism, redox balance, and proliferation, yet its redox activity generates reactive oxygen species (ROS) that can damage DNA, proteins, and lipids. Cancer cells exploit iron homeostasis mechanisms, including iron regulatory proteins, ferritinophagy, and hypoxia-inducible factors to maintain high intracellular iron, supporting metabolic reprogramming, antioxidant defenses, and therapy resistance. Iron-dependent lipid peroxidation drives ferroptosis, a regulated form of cell death uniquely dependent on iron. Ferroptosis is tightly controlled by metabolic and antioxidant pathways and mitochondrial ROS, as well as by lipid composition and polyunsaturated fatty acid availability. Ferroptosis also intersects with apoptosis and necroptosis, highlighting the central role of iron in cell fate and survival. Dysregulation of these pathways in cancer can sensitize cells to ferroptosis, creating a therapeutic vulnerability. Exploiting ferroptosis through modulation of iron availability, redox defenses, or lipid metabolism offers a promising anticancer strategy. However, tissue-specific iron dynamics, tumor heterogeneity, and interactions within the tumor microenvironment complicate clinical translation. Integrative approaches combining metabolic profiling, genetic analysis, and ferroptosis-targeted interventions will be critical to harness iron-dependent cell death while minimizing systemic toxicity. In this review, we explore the mechanisms through which cancer cells sustain high iron, evading associated toxicities and possible implications for integrating ferroptosis based therapies in clinical oncology.

Ferroptosis has emerged over the past decade as a compelling therapeutic avenue for cancer, prompting intense interest in strategies that selectively induce or inhibit this form of cell death. Although substantial progress has been made in identifying genes that regulate ferroptosis sensitivity and in developing small-molecule modulators, it remains unclear which molecular targets offer the greatest therapeutic potential in specific tissues and contexts. Here, we highlight fundamental differences between in vitro and in vivo ferroptosis modulation, with emphasis on the integration of different techniques, mouse models, and how the tumor microenvironment shapes two major ferroptosis surveillance pathways: glutathione peroxidase 4 and ferroptosis suppressor protein 1. We propose that integrating in vivo biological constraints and microenvironmental complexity is essential for the rational design and successful translation of ferroptosis-targeted therapies.

Glaucoma is an ocular disease and a leading cause of irreversible blindness, driven by progressive retinal ganglion cell (RGC) loss. While elevated intraocular pressure (IOP) is a major risk factor, RGC degeneration often persists despite effective IOP-lowering therapy. This persistence suggests the involvement of pressure-independent pathogenic mechanisms. Growing evidence implicates ferroptosis – an iron-dependent, oxidative form of regulated cell death –as a critical contributor to RGC loss in glaucoma. It is characterized by iron accumulation, lipid peroxidation, antioxidant (glutathione) depletion, and mitochondrial dysfunction in degenerating RGCs. Dysregulated iron metabolism and nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy promote iron overload. Simultaneously, impairment of the glutathione-GPX4 axis compromises lipid peroxide detoxification, which converges with oxidative stress and glutamate excitotoxicity, to drive a self-amplifying cycle of RGC ferroptotic death. Preclinical studies show that ferroptosis inhibitors, iron chelators, NRF2 activators, MAPK inhibitors, hydrogen sulfide donors, and natural antioxidants protect RGCs and preserve retinal function. These findings highlight ferroptosis as a promising therapeutic target. Targeting ferroptotic pathways, either alone or in combination with IOP-lowering strategies, may improve long-term visual outcomes. Future research should focus on optimizing therapeutic combinations, assessing safety, and facilitating clinical translation.

Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and cellular antioxidant defenses, is a critical driver of various pathological states. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) serves as the master regulator of redox homeostasis, counteracting oxidative stress by orchestrating the expression of genes involved in glutathione biosynthesis, iron metabolism, and lipid peroxidation detoxification. Recently, the specific induction of lipid peroxidation has been identified as the hallmark of ferroptosis, a form of regulated cell death that represents a promising vulnerability for cancer therapy. However, cancer cells frequently hijack the NRF2 pathway to suppress ferroptosis, thereby promoting tumor survival, metastasis, and therapy resistance. Here, we comprehensively summarize the multi-layered regulatory mechanisms of NRF2, spanning transcriptional, post-transcriptional, and post-translational modifications, within the specific context of the ferroptosis-cancer axis. We further discuss how aberrant NRF2 signaling confers ferroptosis resistance in malignancy and highlight emerging therapeutic strategies that target the NRF2 pathway to reignite ferroptotic cell death in tumors. A deeper understanding of these regulatory networks is essential for the development of precision ferroptosis-based cancer therapies.

Sulfur, like oxygen, belongs to group 16 of the periodic table and exhibits remarkable versatility in both electron donation and acceptance, as well as in its wide range of oxidation states. These properties enable sulfur to participate in diverse redox reactions, while also serving as a critical component of enzyme active sites and redox sensors. Moreover, sulfur is the only element capable of forming stable linear homonuclear chains, a property known as catenation, which gives rise to a rich array of naturally occurring allotropes with complex chemical architectures. Recent advances in analytical technologies have uncovered the in vivo existence of supersulfides, molecules containing catenated sulfur atoms, whose physiological functions and pathological relevance are now beginning to be elucidated. In this review, we highlight the unique chemical features and biological functions of supersulfur species, with a particular focus on their roles in cancer. Furthermore, we discuss the therapeutic implications of supersulfur-driven “reductive stress,” a distinct imbalance in redox homeostasis that may be exploited for cancer treatment.

Ferroptosis, a non-apoptotic regulated cell death culminating in iron-dependent lipid peroxidation, has rapidly emerged as an additional mechanism of neuronal death after stroke. Yet, despite converging molecular features, such as the collapse of antioxidant systems and oxidation of lipids, the upstream biochemical landscapes that trigger ferroptosis differ across ischemic and hemorrhagic injury. In this review, we examine ferroptosis as an emergent property of redox network failure, where the transcriptional, metabolic, and oxidative circuits that normally sustain neuronal resilience are interrupted. Cells continuously operate within a spectrum of oxidative eustress and distress, balancing reactive species that serve as physiological signals and limiting their ability to inflict irreversible damage. Within this continuum, eustress supports adaptive redox signaling, metabolic coupling, and repair, whereas distress reflects exhaustion of reducing power and a shift toward self-propagative oxidation. Drawing on evidence from our lab and others, we explore how distinct stress inputs drive neurons and glia along this continuum toward ferroptotic collapse following each stroke subtype; much of this work originated within reductionist in vitro ferroptotic models and has since been extended to in vivo models. Understanding ferroptosis after stroke not only as a graded failure of redox homeostasis but also an evolutionarily adapted mechanism to couple neuronal injury to the reparative immune response is essential. Effective neuroprotective strategies will therefore depend on identifying and targeting the context-specific triggers and temporal windows that define each stroke subtype.

Aims: Non-enzymatic autoxidation of polyunsaturated fatty acids (PUFAs), generating numerous toxic by-products implicated in neurodegeneration, aging, and other pathologies, is a key process in ferroptosis. Lipid peroxidation (LPO) can be inhibited by deuterated polyunsaturated fatty acids (D-PUFA), as the rate-limiting step of abstraction of bis-allylic hydrogen atoms is slowed down by replacing the bis-allylic hydrogens with deuteriums. Here, we aimed to assess the protective effect of monounsaturated fatty acids (MUFA), which do not undergo LPO, as compared to that of various D-PUFAs, in a liposomal model of LPO.

Methods: To detect LPO induced by ferrous ions in liposomes, we used the LPO fluorescent probe C11-Bodipy (581/591), in addition to measuring conjugated diene and malondialdehyde accumulation.

Results: By applying the C11-Bodipy (581/591) probe, we found that both 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and 1-stearoyl-2-(11,11-d₂-linoleoyl)-phosphatidylcholine (D2-Lin-PC) protect non-deuterated 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine (H-Lin-PC) liposomes from LPO. Similarly, both POPC and 1-stearoyl-2-(11,11,14,14-D4-linolenyl)-phosphatidylcholine (D4-Lnn-PC) protect 1-stearoyl-2-linolenyl-phosphatidylcholine (H-Lnn-PC), and so does 1-stearoyl-2-(6,6,9,9,12,12,15,15,18,18-d10-docosahexaenoyl)-sn-glycero-3-phosphatidylcholine (D10-DHA-PC). The conjugated diene and malondialdehyde probes also showed similar protective effects of POPC and D-PUFA on LPO in H-Lnn-PC.

Conclusion: Obviously, the presence of non-oxidizable lipids, such as POPC, similar to the deuterated lipids D2-Lin-PC, D4-Lnn-PC, and D10-DHA-PC, leads to a sharp decrease in the length of lateral propagation of chain reactions in lipid membranes, but they do not participate in LPO themselves.

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Recent evidence indicates that ferroptosis is a critical player associated with cell death and inflammatory processes in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, as well as in chronic inflammation. In addition, during aging, the expression and activity of various proteins and cellular processes associated with the ferroptotic pathway, such as lipid peroxidation, have been shown to be altered. In this review, we introduce the concept of xenoferroptosis, a process in which ferroptotic signalling is amplified through the combined action of distinct challenges: one involving sub-threshold ferroptosis-related mechanisms, and another involving sub-toxic levels of exogenous or endogenous stressors. Exogenous challenges, such as air pollutants, pesticides, and micro- or nanoplastics, can disrupt redox balance through increased reactive oxygen species production, and impaired antioxidant defences. Endogenous triggers could include misfolded, aggregated proteins, such as amyloid-beta, hyperphosphorylated tau, and alpha-synuclein, which sensitize cells by promoting redox imbalance and mitochondrial dysfunction. While each individual stressor, either endogenous/exogenous or ferroptotic-associated process, may be sublethal, their convergence would initiate a synergistic cascade that accelerates cell death. We propose that xenoferroptosis represents a distinct pathogenic axis at the intersection of molecular pathology and environmental exposure, offering new perspectives for therapeutic interventions that target its dual-trigger mechanisms.

Ferroptosis, an iron-dependent form of regulated cell death (RCD) driven by lipid peroxidation, has been extensively studied since its conceptualization in 2012 and has been suggested as a therapeutic target in many cancers and degenerative diseases. However, three fundamental questions remain unanswered about ferroptosis. First, the mechanisms by which cells execute death during ferroptosis remain elusive: The key role of lipid peroxides in triggering ferroptosis is established, but how this results in the death of a cell remains unclear. Second, the physiological role of ferroptosis throughout the human life cycle is unclear; currently, there is evidence for ferroptosis in early development, immunity, aging, and tumor suppression, but not in many other aspects of physiology. Third, and finally, the intersection between ferroptosis and other RCD modalities, such as apoptosis, necroptosis, pyroptosis, and autophagic cell death, is necessary for understanding how ferroptosis integrates into networks controlling cellular fate. Addressing these gaps in knowledge is essential for building a comprehensive understanding of this mode of cell death, as well as translating ferroptosis knowledge into effective therapeutics.

Osteoarthritis (OA) is increasingly regarded as a whole-organ disease that includes different subsets of joint pathological conditions with variable genetic, biochemical and clinical characteristics. The pathogenesis of OA is perplexing, and disease-modifying drugs are still lacking. Glutathione peroxidase 4 (GPX4), recently best known as the key regulator of ferroptosis implicated in many diseases, including OA, actually has long been identified and reportedly possesses multiple significant biological functions. However, the relationship between GPX4 and OA remains to be elucidated. In this review, we first summarize the current knowledge of GPX4 as a selenoenzyme and the regulation of its expression. Then we scrutinize various possible patterns of involvement of GPX4 in OA. Finally, we also underscore the potential implications and prospects of GPX4-based therapeutic regimens for OA.

Ferroptosis is, in many ways, the odd one out among cell death modalities. It does not, at least as far as we know, require an activating signal. Instead, it represents a default cellular fate that is continuously repressed by a multilayered network of surveillance systems. At its core, ferroptosis is driven by the unchecked peroxidation of polyunsaturated phospholipids (PUFA-PLs), a vulnerability shaped by lipid bilayer composition. Glutathione peroxidase 4 (GPX4) is a central defense enzyme that reduces lipid hydroperoxides to their corresponding alcohols using glutathione as a cofactor. This is complemented by ferroptosis suppressor protein-1 (FSP1)-mediated regeneration of coenzyme Q₁₀ or vitamin K at the plasma membrane and reinforced by dietary or endogenous radical-trapping antioxidants, such as vitamin E, squalene, and 7-dehydrocholesterol. Still, ferroptosis sensitivity is not just a function of antioxidant failure but also a direct consequence of the architecture of the membrane itself: the abundance of PUFA-PLs, shaped by acyl-CoA synthetases like ACSL4 and others; the relative scarcity or abundance of monounsaturated fatty acids, which confer resistance; the regulation of membrane repair and remodeling enzymes; and the delicate balance of redox-active iron within organelles such as lysosomes. Together, these elements converge to determine whether ferroptosis remains a manageable threat or becomes lethal. Despite growing mechanistic insights, fundamental riddles endure: Why does ferroptosis exist at all? What is the precise role of iron: catalyst, signal, or inherent peril? Where, within the cell or organism, does ferroptosis ignite? Can we safely harness this pathway for clinical benefit? And ultimately, is ferroptosis truly a form of regulated cell death, or the mere emergence of a primordial biochemical vulnerability? Inspired by Douglas Green’s iconic riddle framework, this review distils five unresolved questions that may define the coming decade of ferroptosis research. Rather than solving them, we aim to refine their silhouettes at the intersection of lipid (bio)chemistry, evolutionary biology, and translational opportunity.

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a crucial tumor suppressive mechanism and a promising therapeutic target in oncology. This review synthesizes the current understanding of its core molecular machinery, encompassing lipid metabolism, iron homeostasis, and multi-layered cellular defense systems. We highlight the unique metabolic and genetic vulnerabilities that render specific cancer cell types intrinsically susceptible to ferroptosis. Furthermore, we discuss the dynamic propagation of ferroptotic signals within the tumor microenvironment and their complex immunomodulatory effects. Central to this review is a strategic framework for targeting ferroptosis, synthesizing recent advances in the development of specific ferroptosis inducers and evaluating their synergistic potential when combined with chemotherapy, radiotherapy, targeted therapy, and immunotherapy. By integrating mechanistic insight with translational perspectives, this work provides a systematic guide for rationally exploiting ferroptosis in cancer treatment.

Accurate measurement of cysteine and related thiol-containing metabolites is essential for understanding cellular redox regulation. However, the intrinsic reactivity and instability of cysteine present substantial analytical challenges. This review summarizes the biochemical context of cysteine and glutathione metabolism, emphasizing their dynamic redox equilibria and physiological relevance. We critically examine existing analytical approaches, including mass spectrometry-based, enzyme-coupled, and colorimetric methods, and discuss their respective strengths and limitations. Particular attention is given to sample preparation, derivatization strategies, and reagent selection, as these steps are crucial for preserving native thiol-disulfide status. Among various alkylating agents, N-ethylmaleimide is identified as the most reliable for thiol stabilization in liquid chromatography–mass spectrometry (LC-MS) workflows, while specific reagents such as monobromobimane or β-(4-hydroxyphenyl)ethyl iodoacetamide (HPE-IAM) are required for persulfide and polysulfide detection. The review also highlights the pitfalls of using indirect surrogates—such as glutathione or cystathionine levels—to infer cysteine availability, which can lead to significant misinterpretation of metabolic states. We conclude that direct LC-MS-based quantification of cysteine and glutathione, combined with careful derivatization and sample handling, remains the most reliable and accurate approach currently available for the assessment of thiol metabolism and redox homeostasis.

Iron occupies a paradoxical position in biology: indispensable for life through enabling electron transport in metabolism, yet equally capable of driving cellular death. This is exemplified when ferroptosis was defined in 2012 by Dixon and Stockwell (built on parallel work by Marcus Conrad) as a distinct form of regulated cell death. Crucially, ferroptosis is not simply cell death caused by iron poisoning (i.e., iron overload); rather, the ‘dependency of iron’ is evidenced by specific iron chelators that inhibit the induction of death by agents that disrupt cellular redox control (e.g. erastin, which depletes cellular glutathione, and RSL3, which inhibits GPX4 activity, and others). Still, the etymological emphasis on iron does not fully capture the complexity of ferroptosis, which involves a network of potentially lethal metabolic processes encompassing lipids, thiols, and reactive oxygen species. Adding to this tension, recent negative clinical trials of iron chelators in degenerative diseases where ferroptosis has been implicated have tempered enthusiasm for iron-focused strategies and prompted a re-evaluation of iron’s true role in these diseases, and by extension, ferroptosis. In this perspective, we examine the evolving understanding of the ferrum in ferroptosis, its place within the broader metabolic landscape, and its role in neurodegenerative diseases.

Neurons exist at the intersection of two essential yet hazardous metabolic demands: iron-driven bioenergetics and lipid-dependent membrane remodeling. Their reliance on mitochondrial iron for adenosine triphosphate (ATP) generation, combined with the requirement for polyunsaturated fatty acids to sustain synaptic plasticity, creates a biochemical environment primed for ferroptosis. This Perspective examines how the interplay between iron and lipid metabolism defines neuronal vulnerability in neurodegenerative diseases, focusing on apolipoprotein E (ApoE) as a metabolic gatekeeper coordinating those pathways. Beyond its canonical function in lipid transport, ApoE acts as a potent anti-ferroptotic factor by inhibiting ferritinophagy and restraining the release of labile iron, thereby coupling lipid trafficking with iron homeostasis. Dysregulation of this axis in Alzheimer’s disease amplifies lipid peroxidation and compromises antioxidant defenses. Parallel mechanisms are observed in Neurodegeneration with Brain Iron Accumulation disorders, where mutations in lipid-metabolic genes paradoxically lead to brain iron accumulation, underscoring the genetic entanglement of these pathways. Collectively, these findings support a unifying model in which neuronal ferroptosis arises not from isolated iron overload or lipid imbalance, but from the breakdown of a coordinated iron-lipid defense network. We propose that restoring this equilibrium through modulation of ApoE function, preservation of mitochondrial iron utilization, and suppression of lipid peroxidation represents a promising avenue for therapeutic intervention in neurodegenerative disease.

Aims: Endometrial cancer (EC) is often driven by hyperactivation of the PI3K-Akt-mTOR (PAM) pathway due to mutations in PTEN and/or PI3K genes. While mechanistic target of rapamycin complex 1 (mTORC1) inhibitors show limited efficacy as single agents in EC, previous studies suggest that they may sensitize the PAM-mutant cancer cells to ferroptosis, a regulated form of necrosis dependent on iron-catalyzed lipid peroxidation. We investigated whether combining mTORC1 inhibition with ferroptosis induction could overcome resistance mechanisms and improve therapeutic outcomes in EC.

Methods: We evaluated the effect of catalytic, allosteric, and bi-steric mTORC1 inhibition on ferroptosis sensitivity in EC cell lines with different PAM pathway mutational statuses. In vivo efficacy of the combinational treatment was tested in MFE296 xenograft models.

Results: The catalytic and bi-steric mTORC1 inhibitor RMC-6272 sensitized PAM pathway-activated EC cells to ferroptosis induced by GPX4 inhibition, while EC cells without PAM pathway activation were intrinsically sensitive to ferroptosis. Further, mTORC1 inhibition also induced apoptosis in PAM pathway-activated EC cells, indicating a multi-modal cell death response. In vivo, combination treatment with RMC-6272 and the GPX4 inhibitor JKE-1674 significantly suppressed xenograft growth, with evidence of both ferroptosis and apoptosis in tumors.

Conclusion: Our study highlights the therapeutic potential of dual targeting of mTORC1 and ferroptosis to trigger multi-modal cell death in PAM pathway-activated EC, with broader implications for other cancers exhibiting mTORC1 hyperactivation.

Disulfidptosis is a recently identified form of regulated cell death (RCD) triggered by disulfide stress when cystine uptake via solute carrier family 7 member 1 (SLC7A11) overwhelms the cell’s reducing capacity. Unlike apoptosis or other “cell suicide” pathways, disulfidptosis likely represents a “cell sabotage” mechanism, defined by aberrant disulfide bonding and catastrophic actin cytoskeleton collapse. In this Perspective, we examine the paradoxical role of SLC7A11 as both a ferroptosis protector and a disulfidptosis trigger, and the mechanistic hallmarks of disulfidptosis. We highlight emerging therapeutic strategies to target disulfidptosis in cancer, including glucose transporter inhibition, redox-targeting agents, and nanomaterial-based approaches, and consider its dual role in immunity, where it may suppress T cell function yet act as a form of immunogenic cell death. Together, these insights position disulfidptosis as both a conceptual advance in RCD biology and a promising target for cancer therapy that warrants further mechanistic and translational exploration.

Aims: Unique in the broader category of drug-resistant cells, persister cancer cells (PSs) acquire their tolerance to compounds through reversible, chromatin-mediated changes, allowing them to ‘persist’ in the face of cancer therapeutic agents. PSs are implicated in minimal residual disease from which cancer relapse occurs, and given their established sensitivity to ferroptosis, PSs present a critical point through which identification and targeting of drug-resistant cancers may be possible. Ferroptosis sensitivity in drug-resistant cancers may be caused by the attainment of the persister state, or it may merely be correlative with this state and due instead to extended inhibition of oncogenic signaling or the induction of chemotherapy stress. Nonetheless, ferroptosis sensitivity has emerged as a common phenotype across multiple PS and drug-resistant cancer cell types. Identifying biomarkers for and drivers of ferroptosis sensitivity in drug-resistant and PS cells is therefore a high priority.

Methods: We derived PS cells from the lung carcinoma cell line PC9 (PS^PC9), performed transcriptomic analysis, and subsequently lipidomics on the PC9/PS^PC9 system. Additionally, we reverted PS^PC9 cells to the ferroptosis-resistant parental state (PC9^{PS -> PC9}) and assessed the resulting lipid changes. We generated two additional PS-like cell models: PS-like prostate carcinoma (PS^LNCaP) from LNCaP cells and PS-like fibrosarcoma (PS^HT1080) from HT1080 cells, with lipidomics analysis. Finally, we performed a mitochondrial elimination assay and assessed its effect on ferroptosis sensitivity.

Results: We observed enrichment of lipid and sugar metabolism gene expression in PS^PC9; lipidomics revealed enrichment within PS^PC9 for ferroptosis-driving diPUFA phospholipids (diPUFA-PL), as well as polyunsaturated free fatty acids (PUFA FFAs). Upon PS^PC9 reversion to the ferroptosis-resistant parental state (PC9^{PS -> PC9}), this lipid signature reverted. The LNCaP and HT1080 PS-like models individually showed features consistent with PS, including an increased labile-iron pool, reversibility, and enhanced ferroptosis sensitivity, and had lipid features consistent with those in PS^PC9. Finally, mitochondrial elimination partially abrogated ferroptosis sensitivity and altered the PS lipid profile.

Conclusion: In summary, lipidomic changes dependent on the presence of mitochondria are key to the ferroptosis sensitivity of drug-tolerant persister cancer cells.