Rutin ameliorates hepatic ischemia-reperfusion injury by targeting CD36 to suppress hepatocyte ferroptosis

Liver transplantation, the only curative option for end-stage Liver Disease, is limited by Ischemia-Reperfusion Injury, with hepatocyte Ferroptosis as a key pathogenic mechanism. CD36, a fatty acid translocase, drives the progression of multiple liver diseases. Yet, its role in hepatic Ischemia-Reperfusion Injury (HIRI) and Ferroptosis remains unclear. In this study, we generated full and hepatocyte-specific CD36 knockout mice to investigate its impact on HIRI. A significant upregulation of CD36 was observed in Livers following ischemia-reperfusion (I/R) injury and in primary hepatocytes after hypoxia-reoxygenation (H/R). CD36 knockout alleviated Liver Injury and Ferroptosis in HIRI models. In vitro, CD36 silencing suppressed H/R induced Ferroptosis. Furthermore, our results establish rutin, a flavonoid derived from Gardenia, as a novel inhibitor of hepatocyte CD36 that alleviates HIRI. Mechanistically, CD36 regulates fatty acid binding protein 5 (FABP5) to reprogram Lipid Metabolism and drive Ferroptosis in HIRI. Additionally, Rutin suppresses CD36 transcription through the stabilization of hepatocyte nuclear factor 4 α (HNF4α). Our findings demonstrate that CD36 exacerbates HIRI by regulating FABP5-mediated Lipid Metabolism and Ferroptosis, while rutin exerts protective effects via CD36 inhibition. These results highlight the therapeutic potential of rutin for HIRI and identify the CD36/FABP5 axis as a novel target for intervention.