Astragaloside IV Mitigates Hepatocyte Apoptosis in Metabolic Dysfunction–Associated Fatty Liver Disease Through Inhibition of CASP3 ‐Dependent PARP1 Cleavage

Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with hepatic lipid accumulation, inflammation, and hepatocyte apoptosis. Astragaloside IV (AS-IV) has been reported to regulate lipid metabolism, but its effects on hepatocyte apoptosis in MAFLD remain unclear. We investigated the effects of AS-IV in db/db mice and free fatty acid (FFA)-treated HepG2 cells using biochemical assays, histological staining, measurements of inflammatory markers and reactive oxygen species, and apoptosis assays. Network pharmacology and molecular docking were used to identify candidate targets, followed by analyses of CASP3 and PARP1 expression and cleavage and CASP3 overexpression experiments. AS-IV reduced hepatic and cellular triglyceride accumulation, inflammatory markers, and hepatocyte apoptosis, and improved liver histology and serum markers of liver injury in db/db mice. These effects were accompanied by reduced CASP3 activation and PARP1 cleavage. In HepG2 cells, AS-IV also attenuated the changes associated with CASP3 overexpression. Together, these findings suggest that suppression of CASP3-associated PARP1 cleavage may contribute to the protective effects of AS-IV in these experimental models of MAFLD.