ASGR1 exacerbates MASLD by inducing hepatocyte senescence via lysosomal dysfunction and HIF-1α stabilization.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease with limited therapeutic options. Hepatocyte senescence is a critical driver of MASLD progression, but its upstream regulators remain poorly understood. This study aims to investigate the role and mechanism of high expression of asialoglycoprotein receptor 1 (ASGR1) in MASLD-associated hepatocyte senescence. APPROACH AND RESULTS: ASGR1 expression was assessed in liver tissue from patients with chronic liver disease and mice with MASLD induced by a high-fat diet (HFD). ASGR1 knockout (Asgr1-/-) mice and ASGR1-silenced AML12 cells were used to evaluate metabolic and senescent phenotypes. We found that ASGR1 was significantly upregulated in MASLD patients and HFD-fed mice. ASGR1 deficiency markedly reduced body and liver weight, improved glucose tolerance, lowered serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG), and homocysteine (Hcy) levels, and alleviated hepatic steatosis and inflammation in HFD-fed mice. Mechanistic exploration suggested that high expression of ASGR1 was associated with disrupted lysosomal integrity, as evidenced by reduced lysosomal function, which correlated with hypoxia inducible factor-1α (HIF-1α) protein stabilization and nuclear accumulation. This, in turn, activated the p53/p21 senescence axis. Knockdown of ASGR1 restored lysosomal function, decreased HIF-1α levels, and attenuated hepatocyte senescence. CONCLUSIONS: High expression of ASGR1 drives hepatocyte senescence in MASLD, with the underlying mechanisms involving lysosomal dysfunction and HIF-1α stabilization. Targeting the ASGR1-lysosome-HIF-1α-senescence axis represents a promising therapeutic strategy for MASLD.