Yakuchinone A alleviates hepatic ischemia-reperfusion injury in aging livers via the SESN2/AKT1/NRF2 pathway

BACKGROUND: Aged donor livers are highly susceptible to hepatic ischemia-reperfusion injury (HIRI), which significantly limits their clinical utility. While ferroptosis contributes to HIRI, the specific regulatory failure that drives age-related vulnerability remains unclear. Yakuchinone A (YakA) has shown antioxidant potential, but its precise pharmacological target and its ability to modulate intrinsic defense axes in aged livers have not been established. This study aimed to determine if YakA alleviates HIRI by targeting the SESN2/AKT1/NRF2 signaling axis to suppress ferroptotic cell death. METHODS: C57BL/6 mice were subjected to partial HIRI. The role of Sestrin2 (SESN2) was validated through hepatocyte-specific AAV-mediated overexpression or knockdown. The AKT1/NRF2 axis was evaluated using pharmacological agonists and inhibitors. YakA's therapeutic efficacy and its dependence on SESN2 were assessed in vivo and in primary hepatocytes using rescue-of-function experiments. RESULTS: Single-cell RNA-seq and clinical data identified SESN2 as a parenchymal-specific marker of age-dependent HIRI vulnerability, with its expression markedly downregulated in livers following injury. Mechanistically, SESN2 directly binds to AKT1 and promotes its phosphorylation at Ser473, which stabilizes and activates NRF2 to inhibit ferroptosis. YakA treatment significantly upregulated SESN2 expression and reactivated the AKT1/NRF2 defense cascade. Critically, the hepatoprotective effects of YakA were almost entirely abolished following SESN2 knockdown in vivo, identifying SESN2 as its indispensable primary pharmacological target. CONCLUSIONS: YakA protects livers from ischemia-reperfusion injury by targeting the SESN2/AKT1/NRF2 pathway to inhibit ferroptosis. This study redefines the molecular failure of the aging liver and establishes YakA as a promising therapeutic candidate for enhancing aged donor liver transplantation outcomes by restoring this vital regulatory axis.