BRCA1 and BRCA2 deficiencies are classically defined by impaired homologous recombination–mediated DNA repair; however, their pathological consequences extend far beyond cell-autonomous genomic instability. Accumulating evidence indicates that BRCA deficiency is accompanied by iron dysregulation and persistent lipid peroxidation, placing cells under chronic ferroptotic pressure. Studies using BRCA1/2 rat models demonstrate that ferroptosis functions as a decisive biological checkpoint with gene-specific outcomes. Under BRCA1 haploinsufficiency, iron-driven oxidative stress accelerates carcinogenesis by selecting for ferroptosis-resistant clones, whereas BRCA2 haploinsufficiency enhances ferroptotic execution, thereby preventing iron-induced cancer promotion. In contrast, reproductive tissues lacking adaptive escape capacity manifest BRCA deficiency as a direct ferroptosis-driven cellular loss, resulting in male and female infertility. Importantly, ferroptosis is not a silent, cell-confined event. Experimental evidence from asbestos-induced carcinogenesis demonstrates that macrophages undergoing ferroptosis after asbestos phagocytosis release CD63-positive, ferritin-containing extracellular vesicles (EVs) that induce oxidative stress in recipient mesothelial cells, establishing EVs as active mediators of ferroptotic stress propagation. We propose that BRCA deficiency generates a state of ferroptotic priming in which oxidized lipids, iron-related factors, and nucleic acids are disseminated via EVs, thereby shaping tissue- and organ-level pathology. From an evolutionary perspective, the persistence of pathogenic BRCA variants may reflect adaptive advantages conferred by haploinsufficiency in iron-limited, short-lived ancestral environments; under modern conditions of iron abundance and extended lifespan, this once-adaptive state becomes maladaptive, predisposing carriers to cancer and degenerative disorders beyond the cell.

Ferroptosis is an iron-dependent form of regulated cell death, driven by the extensive peroxidation of cellular membrane phospholipids, particularly those enriched with oxidation-sensitive polyunsaturated fatty acids. Given its role in diverse pathologies, ferroptosis inhibition represents a compelling therapeutic target. Among the strategies being explored, modulating cellular membrane lipid composition through exogenous supplementation with less oxidizable fatty acids, such as monounsaturated fatty acids, has gained significant attention. Nevertheless, the influence of endogenous regulators on membrane lipid dynamics and ferroptosis susceptibility is not yet fully elucidated and represents a fertile frontier for discovery. While the gut microbiota is well established as a systemic regulator of host physiology, its potential role in modulating membrane lipid composition and ferroptosis susceptibility remains largely unexplored. This Perspective opens by examining the study by Zhang et al., which suggests that bacterial extracellular vesicles (BEVs) from the gut commensal Lactobacillus amylovorus deliver oleic acid to the mammary gland. This mechanism suppresses ferroptosis and helps sustain lactation in mice under oxidative stress. The work provides a proof-of-concept for BEVs as endogenous lipid delivery vectors that may modulate ferroptosis susceptibility across different organs. Building on these findings, this Perspective critically evaluates the conceptual advance represented by Zhang et al. and integrates it with the broader literature and future scientific opportunities. Specifically, the Perspective dissects the mechanistic underpinnings of this pathway within the context of extracellular vesicle biology and inter-organ lipid trafficking. It also maps the unresolved questions poised to shape the future of the field and examines the key translational hurdles that must be overcome to harness BEV-mediated lipid delivery for therapeutic benefit.

Heme homeostasis influences mitochondrial metabolism and leukemia stem cell biology in acute myeloid leukemia. Lewis et al. uncover a surprising metabolic vulnerability in acute myeloid leukemia: suppression of heme biosynthesis primes leukemic cells for cuproptosis, a form of copper-dependent cell death. By linking heme depletion to mitochondrial cytochrome c oxidase (Complex IV) dysfunction, copper accumulation, and cuproptosis, the study integrates transcriptional regulation, mitochondrial metabolism, and metal homeostasis into a unified framework for selective cancer cell killing.

BRCA1 and BRCA2 deficiencies are classically defined by impaired homologous recombination–mediated DNA repair; however, their pathological consequences extend far beyond cell-autonomous genomic instability. Accumulating evidence indicates that BRCA deficiency is accompanied by iron dysregulation and persistent lipid peroxidation, placing cells under chronic ferroptotic pressure. Studies using BRCA1/2 rat models demonstrate that ferroptosis functions as a decisive biological checkpoint with gene-specific outcomes. Under BRCA1 haploinsufficiency, iron-driven oxidative stress accelerates carcinogenesis by selecting for ferroptosis-resistant clones, whereas BRCA2 haploinsufficiency enhances ferroptotic execution, thereby preventing iron-induced cancer promotion. In contrast, reproductive tissues lacking adaptive escape capacity manifest BRCA deficiency as a direct ferroptosis-driven cellular loss, resulting in male and female infertility. Importantly, ferroptosis is not a silent, cell-confined event. Experimental evidence from asbestos-induced carcinogenesis demonstrates that macrophages undergoing ferroptosis after asbestos phagocytosis release CD63-positive, ferritin-containing extracellular vesicles (EVs) that induce oxidative stress in recipient mesothelial cells, establishing EVs as active mediators of ferroptotic stress propagation. We propose that BRCA deficiency generates a state of ferroptotic priming in which oxidized lipids, iron-related factors, and nucleic acids are disseminated via EVs, thereby shaping tissue- and organ-level pathology. From an evolutionary perspective, the persistence of pathogenic BRCA variants may reflect adaptive advantages conferred by haploinsufficiency in iron-limited, short-lived ancestral environments; under modern conditions of iron abundance and extended lifespan, this once-adaptive state becomes maladaptive, predisposing carriers to cancer and degenerative disorders beyond the cell.

Ferroptosis is an iron-dependent form of regulated cell death, driven by the extensive peroxidation of cellular membrane phospholipids, particularly those enriched with oxidation-sensitive polyunsaturated fatty acids. Given its role in diverse pathologies, ferroptosis inhibition represents a compelling therapeutic target. Among the strategies being explored, modulating cellular membrane lipid composition through exogenous supplementation with less oxidizable fatty acids, such as monounsaturated fatty acids, has gained significant attention. Nevertheless, the influence of endogenous regulators on membrane lipid dynamics and ferroptosis susceptibility is not yet fully elucidated and represents a fertile frontier for discovery. While the gut microbiota is well established as a systemic regulator of host physiology, its potential role in modulating membrane lipid composition and ferroptosis susceptibility remains largely unexplored. This Perspective opens by examining the study by Zhang et al., which suggests that bacterial extracellular vesicles (BEVs) from the gut commensal Lactobacillus amylovorus deliver oleic acid to the mammary gland. This mechanism suppresses ferroptosis and helps sustain lactation in mice under oxidative stress. The work provides a proof-of-concept for BEVs as endogenous lipid delivery vectors that may modulate ferroptosis susceptibility across different organs. Building on these findings, this Perspective critically evaluates the conceptual advance represented by Zhang et al. and integrates it with the broader literature and future scientific opportunities. Specifically, the Perspective dissects the mechanistic underpinnings of this pathway within the context of extracellular vesicle biology and inter-organ lipid trafficking. It also maps the unresolved questions poised to shape the future of the field and examines the key translational hurdles that must be overcome to harness BEV-mediated lipid delivery for therapeutic benefit.

Heme homeostasis influences mitochondrial metabolism and leukemia stem cell biology in acute myeloid leukemia. Lewis et al. uncover a surprising metabolic vulnerability in acute myeloid leukemia: suppression of heme biosynthesis primes leukemic cells for cuproptosis, a form of copper-dependent cell death. By linking heme depletion to mitochondrial cytochrome c oxidase (Complex IV) dysfunction, copper accumulation, and cuproptosis, the study integrates transcriptional regulation, mitochondrial metabolism, and metal homeostasis into a unified framework for selective cancer cell killing.