Hepassocin (HPS) prevents age-related liver senescence and facilitates liver regeneration by activating AMPK via the ANXA2-ERK-p90RSK-LKB1 signaling cascade, and exogenous HPS administration enhances regenerative outcomes in aged mice.
Circulating and intrahepatic HPS levels decline with aging in both mice and elderly humans.
Aged HPS-knockout mice exhibit hepatic steatosis, exacerbated cellular senescence, and impaired autophagy.
Liver regeneration after partial hepatectomy is severely compromised in aged HPS-knockout mice.
HPS directly activates AMPK in hepatocytes through the ANXA2-ERK-p90RSK-LKB1 signaling cascade.
Aged HPS-KO mice exhibit reduced LKB1 and AMPK activation and elevated mTOR activity in both quiescent and regenerating livers.
Treatment with the AMPK agonist AICAR ameliorates the liver aging phenotype and restores liver regenerative capacity in aged HPS-KO mice.
Administration of exogenous HPS enhances regenerative outcomes in aged wild-type mice.
HPS has minimal effects on liver homeostasis in adult mice but plays a critical role in long-term liver maintenance during aging.
This research suggests that a protein called Hepassocin (HPS), which is made and secreted by the liver, plays an important protective role as the liver ages. The study found that levels of HPS drop significantly in older mice and elderly humans, both in the bloodstream and within the liver tissue itself. When researchers engineered mice to lack HPS and then allowed them to age, these mice developed liver fat accumulation, accelerated cellular aging (senescence), and impaired cellular cleanup processes (autophagy). When these aged HPS-deficient mice underwent partial liver removal surgery—a standard way to test the liver's ability to regrow—they experienced higher death rates, less cell growth, and slower liver mass recovery compared to normal aged mice. The study also mapped out how HPS works at the molecular level. HPS activates a protein called AMPK (a key cellular energy sensor) by triggering a chain reaction involving several other proteins (ANXA2, ERK2, p90RSK, and LKB1). When AMPK is activated, it helps suppress another pathway called mTOR, which if overactive can accelerate aging and block cellular recycling. In aged mice lacking HPS, AMPK was underactive and mTOR was overactive—a combination associated with poorer liver health. Treating these mice with a drug that directly activates AMPK reversed many of the aging and regeneration problems, confirming that AMPK is the key target through which HPS acts. Crucially, giving aged normal mice supplemental HPS protein also improved their liver's ability to regenerate after surgery. This research suggests that the natural decline of HPS during aging contributes meaningfully to age-related liver dysfunction and reduced regenerative capacity. Since exogenous HPS treatment improved outcomes in aged mice, therapies that boost HPS signaling—or that activate AMPK through other means—could potentially be developed to help older individuals with liver disease or those needing liver surgery recover more effectively. This could be particularly relevant given that liver disease outcomes tend to be worse in elderly patients.
Yang Y, Chen H, Xiang S, Wei Y, Zhang L, Sun A, et al.. (2026). Hepassocin prevents age-related liver senescence and facilitates liver regeneration by activating AMPK.. Signal transduction and targeted therapy. https://doi.org/10.1038/s41392-026-02773-7