Yingyi Kong

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.

The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. Motivated by our observation of messenger RNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs) and previous findings of increased lipid peroxidation in aged hematopoiesis, we used selenocysteine transfer RNA (tRNASec) gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis. This revealed insights into the protective roles of selenoproteins in preserving HSC stemness and B-lineage maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs’ self-renewal capacity, recapitulating certain aspects of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and pre-B cells. Although Trsp KO activated an antioxidant response transcription factor NRF2, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in pre-B cells of Trsp KO mice, and KO pro-B/pre-B cells displayed differentiation potential toward functional CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B-to-myeloid switch. Given the similarities between the KO model and aged wild-type mice, including ferroptosis vulnerability, impaired HSC self-renewal and B-lineage maturation, and characteristic lineage switch, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and suggest the preventive potential of selenoproteins against aging-related alterations.

Shinya Toyokuni, Yingyi Kong, Hao Zheng, Danyang Mi, Misako Katabuchi, Yashiro Motooka, Fumiya Ito. J Cancer Prev 2021;26:244-9. https://doi.org/10.15430/JCP.2021.26.4.244