Integrative multiomics analysis reveals the ameliorative effects of Xiasangju on metabolic dysfunction-associated steatohepatitis.

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent chronic liver disease for which safe and effective therapeutic options remain scarce. Xiasangju (XSJ), a widely consumed traditional Chinese herbal tea, exhibits diverse pharmacological activities, such as antioxidant, anti-inflammatory, and glucolipid-metabolic regulatory activities. However, its therapeutic potential for MASH has yet to be systematically explored. This study aims to investigate the pharmacological effects of XSJ on a MASH model induced by a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) in mice and to elucidate its potential mechanisms of action. The chemical constituents of XSJ were identified using UPLC-Q-TOF-MS technology. Network pharmacology was employed to predict the potential mechanisms of XSJ in the treatment of MASH. The therapeutic efficacy was evaluated using a CDAHFD-induced mouse model of MASH. Untargeted metabolomics and transcriptomics were utilized to elucidate key regulatory pathways, while RT-qPCR, Western blotting, and molecular docking were used to validate the underlying mechanisms. A total of 74 chemical constituents in XSJ were identified by UPLC-Q-TOF-MS, predominantly phenolic acids and flavonoids. XSJ ameliorated liver injury, lipid deposition, inflammation, oxidative stress, and liver fibrosis in MASH mice. Metabolomic analysis revealed that XSJ could modulate key metabolic pathways, including purine metabolism, arginine biosynthesis, retinol metabolism, and pantothenate and CoA biosynthesis, thereby alleviating liver metabolic dysfunction. Transcriptomic analysis further revealed the regulatory effect of XSJ on the expression of genes related to cholesterol biosynthesis and metabolism, inflammation, and fibrosis. Additionally, XSJ suppressed the progression of liver fibrosis by inhibiting the TGF-β1/Smads and PI3K/AKT/Hmox1 signaling pathways. The findings of this study support the potential of XSJ as a therapeutic agent for MASH, revealing its synergistic mechanisms involving multiple components, targets, and signaling pathways. These results offer valuable insights for the development of novel therapeutic strategies.