Aims: Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a major contributor to neuronal injury following ischemic stroke. Because our previous cancer-cell screens identified ataxia-telangiectasia mutated (ATM), a DNA damage response kinase, as a ferroptosis regulator, we investigated whether ATM inhibition protects neural tissue after ischemic stroke and examined determinants of therapeutic response.

Methods: ATM inhibitors, including the brain-penetrant clinical compound AZD1390, were evaluated in cultured cancer and neuronal cells, oxygen-glucose-deprived organotypic rat and mouse brain slices, and permanent middle cerebral artery occlusion models using multiple inbred and Rabep2-genotype mouse strains. Cell viability, cytotoxicity, lipid peroxidation, ferroptosis-associated markers, infarct volume, and collateral vessel density were assessed. Topical AZD1390 was also tested in mice with impaired collateral networks.

Results: ATM inhibition reduced ferroptosis-associated lipid oxidative injury and protected neurons in multiple preclinical models of stroke. AZD1390 significantly decreased lipid peroxidation, protected neurons from cell death, and limited infarct volume in B6/J and B6/NJ mice, but not in BALB mice. Strikingly, treatment efficacy varied among mouse strains and correlated with differences in the collateral vascular network. The protective effect of systemic AZD1390 was similarly lost in Rabep2-knockout mice with deficient collateral networks. The efficacy of oral AZD1390 was associated with collateral vascular density. Early topical administration also reduced infarct volume in mice with limited collateral networks; however, differences in treatment timing and route prevent direct attribution of this effect to improved local drug delivery.

Conclusion: This work implicates ferroptosis-associated lipid oxidative injury in ischemic neuronal death, identifies ATM inhibition as a candidate translational strategy warranting further mechanistic validation, and highlights collateral vascular anatomy as a potential factor associated with therapeutic response. Collectively, these findings broaden the pathophysiological and translational framework for ferroptosis-targeting strategies in stroke.

Ferroptosis is an iron-dependent form of regulated cell death that has attracted considerable attention as a promising therapeutic strategy because of its ability to eliminate tumor cells. However, tumors are multicellular ecosystems in which malignant cells coexist with diverse stromal and immune cell populations that critically shape tumor progression, anti-tumor immunity, and therapeutic responses. Emerging evidence indicates that ferroptosis exerts fundamentally distinct biological effects across these non-malignant cell populations, extending far beyond direct tumor cell killing. In this review, we propose a cell type-centered conceptual framework in which the consequences of ferroptosis are determined primarily by cellular context rather than by ferroptosis itself. While ferroptosis resistance enables certain cell types, such as fibroblasts and macrophages, within the tumor microenvironment (TME) to maintain tumor-promoting functions, ferroptosis compromises the persistence and effector activity of cytotoxic lymphocytes, including CD8⁺ T cells and natural killer cells. Conversely, ferroptosis in neutrophils and polymorphonuclear myeloid-derived suppressor cells may generate oxidized lipid mediators that paradoxically reinforce immune suppression despite reducing cell abundance. Therefore, in this review, we integrate recent advances in understanding ferroptosis across major nonmalignant cell populations within the TME, focusing on its effects on cell fate, functional plasticity, and anti-tumor immunity. We further discuss how these insights may guide the development of precision ferroptosis-based therapies that selectively target tumor-promoting cell states while preserving protective immune responses.

Aims: Ferroptosis is a form of cell death associated with uncontrolled lipid peroxidation of polyunsaturated fatty acids (PUFAs) leading to membrane destruction. We previously showed that dietary dihomo-gamma-linolenic acid (DGLA) induces ferroptosis in Caenorhabditis elegans germ cells in a dose-dependent manner, and that the sensitivity of germ cells to dietary DGLA is altered by many genetic, dietary, and chemical interventions.

Methods: The severity of germ cell death was documented after dietary supplementation of DGLA, vitamin B12, methionine, and choline, to wild type and mutant C. elegans. The presence of germ cells, gametes, and embryos was visualized in young adult worms with DAPI.

Results: The addition of vitamin B12 rescued DGLA-induced cell death. For this protection, vitamin B12 functions as a cofactor for methionine synthase (METR-1). In addition, dietary methionine and choline rescued germ cell death in the context of low-B12 diets as well as in ferroptosis-sensitive metr-1 and sams-1 mutant strains. The pcyt-1 mutant worms, with reduced capacity for phosphatidylcholine (PC) synthesis, were not responsive to dietary vitamin B12-mediated rescue of DGLA-induced ferroptosis, providing evidence that PC synthesis and homeostasis play key roles in ferroptosis susceptibility. Oleic acid supplementation rescues DGLA-induced cell death in wild type, but not in pcyt-1 mutant strains.

Conclusions: These studies reveal the requirement for dietary vitamin B12 and sufficient PC synthesis in protection from dietary DGLA-induced ferroptosis, highlighting the importance of phospholipid metabolism in ferroptosis regulation.

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Its execution depends not only on the amount of lipid peroxides, but also on where oxidizable lipids, redox-active iron, reactive oxygen species, and antioxidant defenses are distributed within cells. This review summarizes current evidence for organelle-resolved regulation of ferroptosis and oxidative stress, with emphasis on the endoplasmic reticulum, peroxisomes, mitochondria, lysosomes, lipid droplets, and phase-separated condensates. We discuss how lipid remodeling, ether lipid synthesis, mitochondrial metabolism and local antioxidant defense, ferritinophagy, lysosomal lipid peroxidation, and lipid droplet-mediated fatty acid buffering influence ferroptosis sensitivity. We also summarize how organelle-specific redox defenses and stress-adaptive signaling pathways may shape therapeutic responses. Together, these studies show that ferroptosis is regulated by coordinated changes in lipid metabolism, iron handling, and antioxidant capacity across distinct subcellular compartments.

Ferroptosis sensitivity in cancer cells is directly governed by cellular metabolism and nutritional inputs, including amino acid availability, lipid composition, and redox homeostasis. This suggests that dietary interventions might systemically shift the metabolic landscape of tumors toward ferroptotic susceptibility. Specifically, dietary restriction of methionine and cysteine, iron supplementation, selenium or lipid modulation, ketogenic diets, and fasting-mimicking regimens each target distinct aspects of the ferroptosis regulatory network and offer pharmacologic parallels that converge on complementary mechanisms. In glioblastoma (GBM), preclinical studies demonstrate that restriction of dietary methionine and cysteine sensitizes gliomas to ferroptosis and synergizes with glutathione peroxidase 4 (GPX4) inhibitors, while radiation itself triggers ferroptotic cell death. Emerging data extend these principles across multiple tumor types, including pancreatic, gastric, esophageal, and colorectal cancers, as well as leukemia, suggesting broad applicability. Here, we synthesize the rapidly growing literature that links these nutritional interventions to ferroptosis sensitization in cancer, with particular focus on GBM as a paradigmatic treatment-resistant malignancy.

Reactive oxygen species (ROS) are typically elevated at inflammatory sites due to the influx of large numbers of neutrophils and other myeloid cells that produce high levels of oxygen free radicals as microbicidal agents. Reactive oxygen intermediates are also generated as a byproduct of cellular metabolism, due to mitochondrial damage, exposure to toxins or radiation, and are also frequently increased during inflammatory reactions. However, although oxidative stress is often implicated as an initiator or amplifier of inflammation, particularly in the context of cancer, how reactive oxygen modulates inflammatory signalling remains poorly understood. Here we discuss the diversity of pathways and molecules implicated in promoting or suppressing inflammation in response to ROS. As we shall see, reactive oxygen has been reported to influence inflammatory outputs through direct effects on phosphatases that regulate nuclear factor kappa B (NF-κB) activation, through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) or hypoxia-inducible factor (HIF)-1 transcription factors that can directly or indirectly promote inflammatory gene expression, by provoking DNA damage leading to activation of the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)/stimulator of interferon genes (STING) pathway, or through promoting assembly of inflammasomes. Thus, there are a multitude of routes by which ROS can influence inflammatory responses. How reactive oxygen promotes inflammation in specific contexts is likely to be influenced by several factors, including the source of ROS, whether intracellular or extracellular, the responding cell type, as well as the extent of deviation from normal homeostatic setpoints. Understanding how reactive oxygen shapes inflammation has important implications for therapeutic intervention in multiple disease states.

Ferroptosis is an iron-dependent form of programmed cell death defined by the lethal accumulation of lipid peroxides. Accumulating evidence indicates that ferroptosis plays a critical role in a wide range of pathological processes, including tumor progression, ischemia-reperfusion injury, and neurodegenerative diseases. The key determinants of cellular susceptibility to ferroptosis are the homeostasis of iron and lipid metabolism, whose maintenance relies heavily on the precise regulation of inter-organelle communication networks. In this review, we focus on the spatial biology of ferroptosis regulation. From three core dimensions, iron homeostasis modulation, lipid metabolism remodeling, and redox balance maintenance, we systematically dissect the mechanisms by which signal crosstalk and functional coordination among multiple organelles (lysosomes, endoplasmic reticulum, mitochondria, plasma membrane, nucleus, lipid droplets, Golgi apparatus, and peroxisome) govern ferroptosis initiation, signal amplification, and cellular defense responses. Comprehensive elucidation of this multi-organellar coordinated regulatory network will not only advance our fundamental understanding of ferroptosis execution but also provide a holistic perspective for the development of organelle-targeted therapeutic strategies against human diseases.

Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation, and is therefore intrinsically coupled to cellular redox metabolism. Progression of ferroptosis is regulated by an integrated network of metabolic signaling pathways that involve inter-organellar communication. In this Review, we synthesize recent progress in the field that has advanced our understanding of the metabolic determinants of ferroptosis. We discuss key metabolites which participate in the execution and prevention of ferroptosis, describe major signaling axes that impinge on regulating these metabolic activities to determine cellular ferroptosis sensitivity, and highlight how compartmentalized metabolism within and across distinct intracellular organelles collectively shape ferroptosis progression. Together, this Review aims to provide a framework that unifies metabolic state, signaling plasticity and organellar cooperation as a mechanistic basis of ferroptosis, underscoring its implications in the pathogenesis of various diseases including cancer.

Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation. Inducing ferroptosis in tumor cells has emerged as a crucial strategy for cancer treatment and overcoming therapeutic resistance. Ferroptosis suppressor protein 1 (FSP1), identified in recent years, is a key ferroptosis-inhibitory factor that operates independently of glutathione peroxidase 4 (GPX4). FSP1 is highly expressed in multiple malignant tumors, and its expression levels are tightly associated with unfavorable patient prognosis, treatment resistance, and tumor progression. Specific stresses within the tumor microenvironment, including hypoxia, metabolic stress, and the development of drug resistance, can drive a shift in ferroptosis resistance mechanisms from GPX4-dependent to FSP1-dependent pathways. Such plasticity renders FSP1 a druggable target in specific cancer genotypes or at particular stages of tumor progression. Indeed, genetic or pharmacological inhibition of FSP1 has yielded potent antitumor effects across diverse preclinical models. This review systematically summarizes the structural characteristics of FSP1, the molecular mechanisms through which it suppresses ferroptosis, the multilayered regulatory networks controlling its activity, and its roles in different malignancies. We deeply analyze the plasticity of FSP1 dependency in tumor cells in vivo and comprehensively review the latest preclinical progress on small-molecule FSP1 inhibitors and related combinatorial therapeutic strategies. This review aims to establish a theoretical framework to support the clinical translation of FSP1-targeted antitumor strategies.

Selenium is an essential trace element that maintains cellular redox homeostasis through its incorporation into selenoproteins, including glutathione peroxidase 4, a key regulator of ferroptosis. Although selenium deficiency has long been linked to oxidative stress and lipid peroxidation, its significance in the context of ferroptosis has not been fully appreciated. In this review, building on our previous studies, we revisit selenium deficiency and impaired selenoprotein biosynthesis through the lens of ferroptosis. We summarize our findings that selenium deficiency induces a non-apoptotic, vitamin E- and deferoxamine-sensitive form of cell death associated with lipid peroxidation, and that selenium-deficient cells accumulate not only phospholipid oxidation products but also cholesterol oxidation products. We also discuss the possibility that cholesterol oxidation may represent a broader feature of membrane lipid peroxidation, as similar products are observed in cells exposed to the radical initiator. In addition, we highlight SECIS-binding protein 2 deficiency as a human model of impaired selenoprotein biosynthesis, in which increased linoleic acid and cholesterol oxidation products, together with their responsiveness to vitamin E, indicate progressive lipid oxidative damage in vivo. Finally, we discuss recent findings on peroxiredoxin 6 and arsenite, which suggest that toxicological disruption of selenium metabolism can suppress selenoprotein biosynthesis and increase ferroptosis sensitivity. By integrating these findings with recent advances in ferroptosis research, this review provides a perspective on how impaired selenium metabolism contributes to lipid oxidative damage and ferroptotic vulnerability.

Z-nucleic acid-binding protein 1 (ZBP1) is a cytosolic innate immune sensor that detects left-handed Z-DNA and Z-RNA, structures arising from endogenous retroelements, splicing stress, R-loops, viruses, or viral mimicry. Originally viewed as an antiviral receptor, ZBP1 has emerged as a sentinel of genomic and transcriptomic instability. Upon ligand binding, ZBP1 recruits receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and receptor-interacting serine/threonine-protein kinase 3 (RIPK3) via RIP homotypic interaction motif domains; in humans, RIPK1 acts as an essential scaffold to form the necrosome, which phosphorylates mixed lineage kinase domain-like pseudokinase (MLKL) and triggers necroptosis, a lytic, immunogenic cell death. This pathway is intimately regulated by reactive oxygen species (ROS): oxidative stress promotes RIPK1 activation, and necroptosis further drives a mitochondrial ROS burst, establishing a feed-forward amplification loop. In cancer, therapeutic induction of viral mimicry (e.g., using curaxins or splicing inhibitors) combined with tumor-localized ROS generation activates ZBP1-driven necroptosis, leading to the release of damage-associated molecular patterns and tumor antigens. This process converts immunosuppressive “cold” tumors into inflamed “hot” tumors, enhancing dendritic cell maturation, CD8⁺ T cell infiltration, and sensitivity to immune checkpoint blockade. Integrating epigenetic priming, nanomedicine, and patient stratification according to ZBP1/RIPK3/MLKL pathway status holds promise for overcoming therapeutic resistance. Thus, ZBP1-mediated nucleic acid surveillance represents a central innate checkpoint bridging genomic stress to antitumor immunity.

Ferroptosis, an iron-dependent form of regulated cell death characterised by lipid peroxidation, has emerged as a critical pathway in cancer, neurodegeneration, and ischaemia-reperfusion injury. While reverse genetic approaches have dominated ferroptosis research, forward genetic strategies offer unique advantages for discovering novel regulatory mechanisms without prior knowledge of pathway components. This perspective explores how classical forward genetic methodologies, including chemical mutagenesis screens, genetic modifier studies, and quantitative trait locus mapping, can be adapted to systematically identify ferroptosis regulators. We focus on employing the nematode model, Caenorhabditis elegans, and discuss the inherent advantages and disadvantages of this system. Technical considerations for designing phenotype-based screens are discussed, highlighting successful examples from related cell death pathways. Experimental frameworks for leveraging alternate model organisms to uncover conserved ferroptosis mechanisms are also explored. Forward genetics promises to reveal unexpected connections between ferroptosis and cellular processes, potentially identifying new therapeutic targets and biomarkers for ferroptosis-related diseases.

Aims: Brown adipose tissue (BAT) relies heavily on mitochondrial activity and reactive oxygen species homeostasis to regulate thermogenesis and metabolic balance. However, the specific role of glutathione peroxidase 4 (GPX4), a critical antioxidant enzyme and central regulator of ferroptosis, in BAT remains unclear. This study aims to investigate the necessity of GPX4 for the functional integrity and thermogenic capacity of BAT.

Methods: Initially, we employed pharmacological inhibition of GPX4 in vitro using differentiated brown adipocytes. To investigate its role in vivo, we generated a BAT-specific Gpx4 knockout mouse model. The physiological and metabolic impacts of GPX4 deficiency were evaluated across three different conditions: cold exposure, high-fat diet, and vitamin E-deficient diet. Comprehensive evaluations were conducted using metabolic, histological, ultrastructural, and transcriptomic (RNA-seq) analyses.

Results: In vitro, pharmacological inhibition of GPX4 induced ferroptosis in differentiated brown adipocytes, suggesting its potential regulatory role. Strikingly, in vivo histological, ultrastructural, and metabolic analyses indicated that the genetic deletion of GPX4 does not impair BAT morphology or thermogenic function under any of the tested conditions. Consistent with these physiological findings, RNA-seq revealed that GPX4 deficiency did not significantly alter the expression of genes associated with ferroptosis or thermogenic pathways.

Conclusion: Although pharmacological inhibition of GPX4 triggers ferroptosis in brown adipocytes in vitro, GPX4 is not essential for maintaining the morphological integrity and thermogenic capacity of BAT in vivo under the specific experimental conditions tested.

Ferroptosis, a distinct form of cell death driven by lipid peroxidation, holds considerable potential as a therapeutic strategy for cancer. Its unique mechanisms, centered on the disruption of cellular systems that protect against phospholipid peroxidation, distinguish ferroptosis from apoptosis and other well-characterized forms of cell death. This creates a novel therapeutic opportunity; however, it also presents challenges, as non-cancerous cells likewise depend to some extent on ferroptosis-regulating pathways. Consequently, extensive research efforts have focused on identifying suitable molecular targets, developing targeted drug delivery strategies, defining cancer types that are particularly dependent on ferroptosis-regulatory components, and establishing effective patient stratification approaches. Furthermore, exploring combination therapies may further enhance therapeutic efficacy through additive or synergistic effects. This review highlights the potential synergistic effects of combining ferroptosis induction with conventional cancer therapies, including chemotherapy, immunotherapy, and radiation therapy. Preclinical studies indicate that promoting ferroptosis may help overcome drug resistance, a major barrier that often limits the efficacy of existing treatments. Nevertheless, the successful development of ferroptosis-based therapies will require overcoming several challenges through innovative therapeutic strategies.

Friedreich’s ataxia (FRDA) is a rare neurodegenerative condition driven by a severe deficiency of the mitochondrial protein frataxin (FXN). This depletion impairs mitochondrial iron-sulfur cluster biogenesis and disrupts intracellular iron homeostasis, ultimately promoting oxidative stress. Driven by localized iron overload and the continuous generation of reactive oxygen species, the resulting metabolic dysfunction renders vulnerable tissues highly susceptible to ferroptosis. This iron-dependent form of regulated cell death, executed through excessive lipid peroxidation, is now widely acknowledged as an important contributor to the neurodegeneration and hypertrophic cardiomyopathy that characterize FRDA. In the present review, we explore how FXN loss undermines cellular defenses against oxidative damage, placing a specific focus on the regulation of the lipid redox landscape. We detail the breakdown of glutathione (GSH)-dependent mechanisms, specifically highlighting the blunted Nrf2 antioxidant response and the subsequent reduced capacity of glutathione peroxidase 4. Alongside these deficits, we investigate the compensatory roles of GSH-independent rescue networks, namely ferroptosis suppressor protein 1 and mitochondrial dihydroorotate dehydrogenase. Looking toward clinical translation, we critically assess emerging pharmacological interventions designed to target these ferroptotic nodes. The potential of mitochondria-targeted iron chelators, lipoxygenase inhibitors, lipophilic radical-trapping antioxidants, and novel Nrf2 activators is evaluated to determine whether inhibiting ferroptosis can serve as a viable disease-modifying strategy. Moving forward, combinatorial “protect and restore” approaches will likely prove essential for maximizing therapeutic efficacy in FRDA.

Ferroptosis, a lipid peroxidation-driven form of regulated cell death, has emerged as a central mechanism in neurological disease. While most studies have focused on neuronal vulnerability, non-neuronal cells, including oligodendrocytes, astrocytes, microglia, brain endothelial cells, and central nervous system (CNS) infiltrating T cells, play equally critical roles in shaping disease progression. These cell types regulate iron homeostasis, lipid metabolism, antioxidant defenses, and inflammatory signaling, thereby establishing the microenvironmental conditions that determine ferroptotic susceptibility within the CNS. Accumulating evidence demonstrates lipid peroxidation and ferroptosis-related signaling in demyelinating disorders, ischemic injury, small vessel disease, Alzheimer’s disease, Parkinson’s disease, and spinal cord injury. However, the contribution of non-neuronal cells to ferroptotic stress and execution remains comparatively underexplored. In this review, we synthesize emerging data highlighting cell type-specific dependencies on glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferroptosis suppressor protein 1 (FSP1), nuclear factor erythroid 2-related factor 2 (NRF2), peroxiredoxin (PRDX), thioredoxin (TRX), iron-handling proteins, and lipid remodeling pathways, and discuss how these regulatory networks differ across CNS-resident and CNS infiltrating T cells. We propose that ferroptosis in neurological disease is not solely a neuron-autonomous event, but a tissue-level process orchestrated by non-neuronal cells with distinct metabolic and immunological programs. Understanding these cell type-specific vulnerabilities and regulatory mechanisms will be essential for the development of targeted therapeutic strategies aimed at modulating ferroptotic stress in neuroinflammatory and neurodegenerative disorders.

Iron is indispensable for cellular metabolism yet potentially cytotoxic, making its intracellular handling a fundamental determinant of cell fate decisions. The endo-lysosomal system has recently emerged as a central iron rheostat that integrates transferrin uptake, ferritinophagy, and lysosomal iron export to control iron bioavailability for mitochondria and other iron-dependent pathways. Growing studies further show that lysosomal iron is not merely permissive for ferroptosis but can directly initiate lipid damage through localized iron activation, lysosomal lipid peroxidation, and lysosomal membrane permeabilization. At the same time, emerging studies on organelle contact sites reveal that ferroptosis arises from the failure of a coordinated multi-organellar communication system, in which lysosomes, the endoplasmic reticulum, and mitochondria exchange iron, lipids, and redox signals in an effort to metabolically adapt to stress. This perspective is particularly relevant to drug-tolerant persisters and mesenchymal cancer cell states, which rely on rewired lysosomal iron trafficking to sustain plasticity while becoming highly susceptible to ferroptosis. In this minireview, we discuss emerging insights into the spatial organization of iron metabolism and propose a model in which ferroptosis sensitivity depends on the intracellular routing, chemical reactivity, and release dynamics of iron, highlighting lysosomal iron handling as a key therapeutic vulnerability in minimal residual disease.

Ferroptosis is an oxidative form of non-apoptotic cell death that is important for human biology. This process can be induced in cultured cells by at least four structurally and mechanistically distinct classes of ferroptosis inducing (FIN) small molecules. These four classes of FINs are distinguished based on molecular target and mechanism of action. The lethal mechanism of the prototypic oxime-containing class III FIN, FIN56, is unique and poorly understood. FIN56 is proposed to cause ferroptosis by depleting coenzyme Q10 and degrading glutathione peroxidase 4 (GPX4). Curiously, the FIN56 analogs caspase independent lethal 56 (CIL56) and tegavivint also trigger non-apoptotic cell death but not ferroptosis. Tegavivint is a drug candidate currently being tested in humans for the treatment of cancer. Here, we review our understanding of the FIN56 lethal mechanism with a view to guiding future investigations into a privileged chemical scaffold that possesses unusual lethal activity in cancer cells.

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.