Liver aging significantly impairs hepatic function and regenerative capacity, increasing the risk of morbidity and mortality from chronic liver diseases. Identifying molecular regulators of these processes may reveal promising therapeutic targets. Although Hepassocin (HPS), a hepatokine with known hepatoprotective functions, has minimal effects on liver homeostasis in adult mice, its role in long-term liver maintenance remains unclear. In this study, we observed a decrease in circulating and intrahepatic HPS levels in both aged mice and elderly humans. Moreover, the upregulation of HPS following two-thirds partial hepatectomy (PHx) was significantly blunted in 12-month-old (aged) mice. Aged HPS-knockout (KO) mice exhibited variable hepatic steatosis, exacerbated cellular senescence, and impaired autophagy. Liver regeneration after PHx was severely compromised in aged HPS-KO mice, as indicated by increased mortality, reduced hepatocyte proliferation, delayed liver mass recovery, and worsened autophagy disruption. Mechanistically, HPS directly activated 5'-AMP-activated protein kinase catalytic subunit alpha-1 (AMPK) in hepatocytes via the Annexin A2 (ANXA2)-extracellular signal-regulated kinase 2-90 kDa ribosomal protein S6 kinase 1-liver kinase B1 (ANXA2-ERK-p90RSK-LKB1) signaling cascade. Compared with their wild-type littermates, aged HPS-KO mice presented reduced LKB1 and AMPK activation and elevated mechanistic target of rapamycin kinase (mTOR) activity in both quiescent and regenerating livers. Treatment with the AMPK agonist AICAR ameliorated the liver aging phenotype and restored liver regenerative capacity in aged HPS-KO mice. Importantly, the administration of exogenous HPS enhanced regenerative outcomes in aged wild-type mice. These results establish HPS as a novel protective factor against liver senescence through AMPK-dependent mechanisms. Therapeutic strategies aimed at enhancing HPS signaling may offer a viable approach to counteract age-related liver dysfunction and regeneration failure.
