Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health burden, yet effective therapeutic options remain limited. This study investigated the protective mechanisms of Astragalus membranous extract (AM) against high-fat diet (HFD)-induced MAFLD in mice using an integrated strategy combining network pharmacology, hepatic metabolomics, and 16S rRNA sequencing. UPLC–Q-Orbitrap–MS/MS identified 37 major constituents in AM, mainly phenolic acids and flavonoids. Iristectorin A, isorhamnetin, ononin, and rhamnocitrin were identified as key candidate compounds due to their relatively high abundance and confirmation as absorbed constituents in vivo. Network pharmacology and molecular docking indicated favorable interactions with hub targets (TNF, EGFR, and AKT1; binding energies < −5.0 kcal/mol) and highlighted the involvement of the AGE–RAGE signaling pathway and inflammation- and lipid metabolism-related processes. In vivo, AM significantly attenuated HFD-induced weight gain, decreased serum ALT and AST levels, and reduced hepatic lipid deposition. AM also alleviated oxidative stress by lowering malondialdehyde (MDA) and increasing superoxide dismutase (SOD) activity, while suppressing hepatic IL-1β and IL-6. Moreover, AM improved gut microbial homeostasis by restoring α-diversity and enriching beneficial genera, including Akkermansia and Bacteroides. Hepatic metabolomics further showed that AM partially normalized lipid metabolic disturbances, particularly glycerophospholipid and sphingolipid metabolism. Collectively, these results suggest that AM mitigates MASLD via a multi-component, multi-target mechanism, potentially through modulation of AGE–RAGE-associated inflammatory signaling and the gut–liver axis, supporting its development as a functional food-derived candidate for metabolic liver disorders.
An et al. (Sat,) studied this question.