This study investigates the protective effects of silibinin against ischemia-reperfusion-induced acute kidney injury (IRI-AKI) and explores its underlying mechanisms. Silibinin, a polyphenolic flavonoid, has been shown to improve various diseases by inhibiting ferroptosis, a form of iron-dependent cell death. The researchers found that silibinin significantly alleviated renal dysfunction, pathological damage, and inflammation in IRI-AKI mice. Mechanistically, silibinin inhibited ferroptosis both in vivo and in vitro. Proteome microarrays identified FTH1 as a key target of silibinin, which was confirmed through molecular docking, SPR, CETSA, and DARTS. Co-IP assays demonstrated that silibinin disrupted the interaction between FTH1 and NOOA4, inhibiting ferritinophagy. Knockdown of FTH1 in vitro reversed the inhibitory effects of silibinin on ferroptosis. These findings suggest that silibinin effectively alleviates AKI by targeting FTH1 to reduce ferroptosis, indicating its potential as a therapeutic agent for managing and treating AKI.This study investigates the protective effects of silibinin against ischemia-reperfusion-induced acute kidney injury (IRI-AKI) and explores its underlying mechanisms. Silibinin, a polyphenolic flavonoid, has been shown to improve various diseases by inhibiting ferroptosis, a form of iron-dependent cell death. The researchers found that silibinin significantly alleviated renal dysfunction, pathological damage, and inflammation in IRI-AKI mice. Mechanistically, silibinin inhibited ferroptosis both in vivo and in vitro. Proteome microarrays identified FTH1 as a key target of silibinin, which was confirmed through molecular docking, SPR, CETSA, and DARTS. Co-IP assays demonstrated that silibinin disrupted the interaction between FTH1 and NOOA4, inhibiting ferritinophagy. Knockdown of FTH1 in vitro reversed the inhibitory effects of silibinin on ferroptosis. These findings suggest that silibinin effectively alleviates AKI by targeting FTH1 to reduce ferroptosis, indicating its potential as a therapeutic agent for managing and treating AKI.