Selenomethionine as a dual-mechanism ferroptosis inhibitor: selenium-supply-driven GPX4 biosynthesis beyond transsulfuration and reductive-capacity-mediated ROS scavenging independent of GPX4 activity.

Ferroptosis is an iron-dependent form of nonapoptotic cell death driven by lipid peroxidation. The selenium-dependent glutathione peroxidase 4 (GPX4) serves as the central regulator of ferroptosis through enzymatic reduction of phospholipid hydroperoxides (PLOOH). While GPX4 remains the canonical ferroptosis suppressor, whether alternative regulatory axes exist beyond this selenoprotein-mediated pathway remains unclear. In the present study, we identified selenomethionine as a novel resister of ferroptosis induced by RSL3 through screening FDA drug library and natural product library. Mechanistically, selenomethionine serves as a selenium donor for GPX4 biosynthesis beyond the transsulfuration pathway. The anti-ferroptosis activity of selenomethionine persists even after CRISPR-mediated GPX4 knockout, revealing a GPX4-independent mechanism that relies on direct redox modulation via selenium-mediated reactive oxygen species (ROS) scavenging. Significantly, selenomethionine administration effectively mitigated cisplatin-induced acute kidney injury in vivo by suppressing ferroptosis. This work establishes selenomethionine as a unique dual-mechanism ferroptosis suppressor that simultaneously modulates enzymatic antioxidant defense through GPX4 biosynthesis and non-enzymatic radical trapping via selenium-mediated redox cycling, providing new insights into therapeutic strategies for ferroptosis-related pathologies.