Silibinin attenuates ferroptosis in acute kidney injury (AKI) by targeting FTH1. This study demonstrates that silibinin protects against ischemia-reperfusion injury (IRI)-induced AKI by inhibiting ferroptosis. Silibinin, a polyphenolic flavonoid, was found to bind to FTH1, a key iron storage protein involved in ferroptosis. The binding of silibinin to FTH1 disrupted the NCOA4-FTH1 interaction, inhibiting ferritinophagy and thereby reducing ferroptosis. Silibinin treatment significantly alleviated renal dysfunction, pathological damage, and inflammation in IRI-AKI mice. In vitro experiments confirmed that silibinin inhibited ferroptosis by reducing lipid peroxidation, oxidative stress, and mitochondrial damage. Knockdown of FTH1 reversed the protective effects of silibinin, indicating that FTH1 is a critical target for silibinin's anti-ferroptotic action. These findings suggest that silibinin could be developed as a potential therapeutic agent for managing and treating AKI by targeting FTH1 to reduce ferroptosis. The study provides robust evidence supporting the therapeutic potential of silibinin in IRI-AKI.Silibinin attenuates ferroptosis in acute kidney injury (AKI) by targeting FTH1. This study demonstrates that silibinin protects against ischemia-reperfusion injury (IRI)-induced AKI by inhibiting ferroptosis. Silibinin, a polyphenolic flavonoid, was found to bind to FTH1, a key iron storage protein involved in ferroptosis. The binding of silibinin to FTH1 disrupted the NCOA4-FTH1 interaction, inhibiting ferritinophagy and thereby reducing ferroptosis. Silibinin treatment significantly alleviated renal dysfunction, pathological damage, and inflammation in IRI-AKI mice. In vitro experiments confirmed that silibinin inhibited ferroptosis by reducing lipid peroxidation, oxidative stress, and mitochondrial damage. Knockdown of FTH1 reversed the protective effects of silibinin, indicating that FTH1 is a critical target for silibinin's anti-ferroptotic action. These findings suggest that silibinin could be developed as a potential therapeutic agent for managing and treating AKI by targeting FTH1 to reduce ferroptosis. The study provides robust evidence supporting the therapeutic potential of silibinin in IRI-AKI.