Astragaloside IV alleviates metabolic associated fatty liver disease by regulating ferroptosis via the SLC7A11/GPX4 pathway

• AST IV alleviates glucose and lipid metabolism disorders in both high-fat diet-induced MAFLD mice and free fatty acids (FFAs)-exposed HepG2 cells. • Network pharmacology predicts ferroptosis as a key mechanism underlying AST IV’s therapeutic effect against MAFLD. • AST IV reduces oxidative stress in the liver of MAFLD mice and FFAs-induced HepG2 cells. • Activation of the SLC7A11/GPX4 axis inhibits ferroptosis, representing the core mechanism of AST IV-mediated hepatoprotection. Metabolic associated fatty liver disease (MAFLD), characterized by hepatic steatosis and metabolic dysregulation, is the most prevalent chronic liver disease worldwide, yet effective therapeutic strategies remain limited due to its complex pathogenesis. Astragaloside IV (AST IV), a bioactive saponin derived from Astragalus membranaceus, has demonstrated hypoglycemic, lipid-modulating, antioxidative, and hepatoprotective properties—though its specific mechanisms against MAFLD are not fully elucidated. In this study, we established high-fat diet-induced mouse and free fatty acid-induced HepG2 cell models of MAFLD to evaluate the efficacy of AST IV. Serum biochemical analyses revealed that AST IV significantly improved glucolipid metabolism and reduced hepatic injury. Combining network pharmacology prediction with experimental validation, we identified ferroptosis as a key pathway targeted by AST IV. Specifically, AST IV upregulates SLC7A11 and GPX4 expression while downregulating ACSL4, thereby inhibiting ferroptosis. Molecular docking further confirmed strong binding affinities between AST IV and these core proteins. In conclusion, our findings demonstrate that AST IV alleviates MAFLD by suppressing ferroptosis, highlighting its potential as a novel phytochemical candidate for MAFLD intervention.