PRDX6 Regulates Ferroptosis Sensitivity through Cellular Selenium Utilization

Abstract

Glutathione peroxidase 4 (GPX4) is a key enzyme that reduces phospholipid hydroperoxides and thereby protects membrane lipids from oxidative damage, establishing it as a central regulator of ferroptosis. However, whether other peroxidases contribute to ferroptosis protection has remained unclear. We found that cells lacking GPX4 still retain substantial phospholipid hydroperoxide-reducing capacity, suggesting the existence of additional enzymes. Focusing on peroxiredoxin 6 (PRDX6), previously reported to possess such activity, we evaluated its peroxidase function. Although PRDX6 displayed detectable activity, it was markedly weaker than that of GPX4. Strikingly, PRDX6 knockout significantly increased ferroptosis sensitivity in cancer cells. Mechanistic studies revealed that beyond its peroxidase function, PRDX6 acts as a selenium-acceptor protein, facilitating intracellular selenium handling and enhancing efficient selenium incorporation into selenoproteins, including GPX4. This role was confirmed in vivo, as Prdx6-deficient mouse brains exhibited reduced GPX4 expression and PRDX6-deficient tumor xenografts displayed increased ferroptosis sensitivity. Collectively, these findings identify PRDX6 as a critical determinant of ferroptosis sensitivity, not primarily through peroxidase activity, but via its role as a selenium-handling protein that sustains selenoprotein biosynthesis.

graphical abstract