Preoperative Aerobic Exercise Training Protects Against Hepatic Ischemia–Reperfusion Injury Through the MG53–CAV-1 Axis

Abstract Background Hepatic ischemia–reperfusion injury (HIRI) remains a significant clinical challenge in liver surgery and transplantation. Although aerobic exercise training (AET) confers systemic benefits, the mechanisms by which it mitigates HIRI remain poorly defined. Methods Male C57BL/6 mice underwent sedentary housing or 5 weeks of moderate-intensity swimming training before partial hepatic I/R. Liver injury, oxidative stress, apoptosis, iron homeostasis, ferroptosis-associated markers, and hepatic MG53–Caveolin-1 (CAV-1) signaling were evaluated. Hepatic MG53 was silenced using hydrodynamically delivered Ad-shMG53, and TAT–MG53 was administered via the portal vein at the onset of reperfusion. CAV-1-dependent signaling was pharmacologically disrupted with Daidzein. Results Preoperative AET significantly reduced serum ALT and AST, alleviated oxidative stress, and suppressed ferroptotic markers following HIRI. AET increased hepatic MG53 expression, enhanced MG53–Caveolin-1 interaction, and preserved cellular redox homeostasis. MG53 knockdown abolished AET–associated hepatoprotection, whereas TAT–MG53 supplementation restored protective phenotypes. Disruption of Caveolin-1 abrogated the benefits of AET and TAT–MG53 following HIRI. Conclusions Preoperative AET protects against HIRI through an MG53–CAV-1-dependent mechanism that preserves hepatic iron and redox homeostasis and limits oxidative and ferroptosis-associated injury. The MG53–CAV-1 axis may represent a potential perioperative therapeutic target for reducing liver I/R injury.