Selenium metabolism, lipid peroxidation, and ferroptosis sensitivity: Lessons from selenium deficiency

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.