Abstract <p>The interplay between selenium (Se) metabolism and ferroptosis presents a compelling area of study in cancer biology. This review synthesizes the current understanding of key pathways implicated in ferroptosis susceptibility, with a focus on the role of selenoproteins, particularly glutathione peroxidase 4 (GPX4), which mitigates lipid peroxidation and prevents ferroptotic cell death through the system Xc⁻/GSH axis. Additionally, selenoprotein P contributes to Se transport, playing a crucial role in ferroptosis resistance observed in certain cancers. Targeting Se pathways, especially disrupting GPX4 and selenoprotein P functions, offers promising avenues for cancer therapy. The differential dependence of cancer cells on Se and selenoproteins highlights the potential for selective induction of ferroptosis in malignant cells. Future research should focus on unraveling the mechanistic underpinnings of Se-mediated ferroptosis and exploring combinatorial therapeutic strategies. This review sets the stage for innovative approaches that leverage Se metabolism to enhance cancer treatment efficacy through ferroptosis modulation.</p> Key messages <p><UnorderedList Mark="Bullet"> <ItemContent> <p>Selenium (Se) and selenoproteins regulate ferroptosis, a lipid peroxidation–driven form of cell death.</p> </ItemContent> <ItemContent> <p>GPX4, a Se-dependent enzyme, defends cells by neutralizing lipid hydroperoxides.</p> </ItemContent> <ItemContent> <p>Xc⁻/GSH/GPX4 and FSP1-CoQ₁₀ pathways are critical in modulating ferroptosis susceptibility.</p> </ItemContent> <ItemContent> <p>Selenoprotein P, SEPHS2, and SQOR highlight vulnerabilities in Se-dependent cancer cell survival.</p> </ItemContent> <ItemContent> <p>Se’s role in balancing antioxidant defense and ferroptosis offers therapeutic insights.</p> </ItemContent> </UnorderedList></p>