Aqueous Extract of Siraitia grosvenorii Alleviates MAFLD by Modulating Metabolism and Maintaining Gut Homeostasis in High-Fat Diet Fed Mice

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disease worldwide with complex pathogenesis and no approved specific therapy. Siraitia grosvenorii is a widely used medicinal and edible herb, yet its efficacy and underlying mechanisms against MAFLD remain poorly defined. This study explored the protective effects and potential mechanisms of aqueous extract of Siraitia grosvenorii (AESG) on MAFLD. Based on ultra-high-performance liquid chromatography-linear trap quadrupole orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap-MS) analysis, 38 components in AESG were tentatively assigned, with tetracyclic triterpene saponins being the most abundant. In high-fat diet (HFD)-induced MAFLD mice, AESG significantly attenuated body weight gain, reduced plasma total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) levels, and dramatically decreased hepatic triglyceride (TG) accumulation from 0.0141 mmol/g in the model group to 0.0063 mmol/g in the low-dose AESG group, corresponding to a reduction of 55.00%. AESG also alleviated plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and improved hepatocyte steatosis. Furthermore, AESG restored HFD-induced gut dysbiosis by enriching beneficial bacteria including Akkermansia and suppressing harmful bacteria such as Ruminococcus. In free fatty acids (FFA) stimulated HepG2 cells, AESG suppressed de novo lipogenesis via downregulating Fatty Acid Synthase (FASN), Acetyl-CoA Carboxylase (ACC) and Sterol Regulatory Element-Binding Protein 1c (SREBP1c), and enhanced antioxidant capacity via activating the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase 1 (HO-1)/Sirtuin 1 (SIRT1) pathway, thereby attenuating lipid accumulation and oxidative stress. In conclusion, AESG ameliorates MAFLD by inhibiting lipogenesis, improving oxidative stress, and regulating gut microbiota. These findings support Siraitia grosvenorii as a promising natural dietary intervention for MAFLD prevention and adjuvant therapy.