Untargeted Metabolomic Analysis Reveals the Mechanism Underlying <i>Swertia mussotii</i> Treatment on Rats With Non‐Alcoholic Fatty Liver Disease Using UPLC‐Q‐TOF/MS

Swertia mussotii (SM) is a traditional Tibetan medicine and can effectively treat hepatopathies like non-alcoholic fatty liver disease (NAFLD). However, the mechanism by which it alleviates NAFLD is largely undetermined. In this study, we determined the efficacy of SM and its associated mechanism in NAFLD with in vivo and in vitro models. NAFLD was induced in mice by administering the high-fat diet (HFD) and in HepG2 cells via free fatty acid (FFA) stimulation. Treatment with SM significantly reduced body weight, decreased serum lipid levels, alleviated hepatic lipid accumulation, and attenuated liver inflammation and oxidative stress. Integrated untargeted metabolomic analysis was conducted via UPLC-Q-TOF/MS, and the results revealed that SM restored dysregulated metabolic pathways, particularly the TCA cycle and amino acid metabolism. Also, SM activated SIRT1/AMPK axis, leading to the phosphorylation of ACC, the downregulation of SREBP-1c and FASN (the corresponding target), and the upregulation of PPAR-γ, thereby inhibiting de novo lipogenesis while promoting fatty acid β-oxidation. In vivo, metabolites may be the active compounds for pharmacological effects. The above results illustrate SM's multi-target mechanism in treating NAFLD, suggesting its potential as the efficient therapeutic agent and the importance of combining traditional medicine with modern metabolomic studies.