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.

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.