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

KY0418, a bioavailable covalent GPX4 inhibitor, induces ferroptosis in vivo and suppresses tumor growth and metastasis in multiple cancer models.

• Why it matters: Ferroptosis plays a role in various human diseases, but the lack of effective, bioavailable inducers has hindered understanding and therapeutic development.
• What they did: Researchers developed KY0418, a selective covalent inhibitor targeting GPX4 SeCys46, with high plasma stability and broad tissue distribution after oral dosing in mice, and tested its effects on cancer cells and mouse models.
• The result: KY0418 triggers ferroptotic ultrastructural changes, remodels tissue metabolism, and generates hydroxyl radicals, leading to variable tumor growth inhibition (up to 70%) and consistent eradication of circulating tumor cells and metastasis.