A bioavailable GPX4 inhibitor for ferroptosis induction in vivo and tumor suppression.

Ferroptosis is implicated in multiple human diseases, but the lack of bioavailable inducers has limited its physiological study and therapeutic translation. Here, we report KY0418, a selective covalent inhibitor of glutathione peroxidase 4 (GPX4) featuring an isourea warhead, with high plasma stability and broad tissue distribution after oral dosing in mice. KY0418 specifically targets GPX4SeCys46 to induce ferroptosis hallmarks in human and mouse cancer cell lines, with greater selectivity than existing inhibitors. In a standardizable acute-liver-injury mouse model, KY0418 triggers ferroptotic ultrastructural changes matching those of established inducers, and systemic administration remodels tissue metabolism and generates hydroxyl radicals detectable by a chemiluminescent probe. Subcutaneous tumors from different cancers exhibited variable responses to KY0418 treatment, from no effect to about 70% growth inhibition, but KY0418 consistently eradicated circulating tumor cells and suppressed metastasis across multiple cancer models. These findings position KY0418 as a tool for advancing in vivo ferroptosis research and its clinical translation.