Abstract

Ethnopharmacological relevance Metabolic dysfunction-associated steatohepatitis (MASH) constitutes an advancing hepatic disorder endangering worldwide well-being with scarce therapeutic options. Social stress, an important trigger of MASH, exacerbates hepatic inflammation and lipid metabolism disorders. Xiaoyaosan (XYS), a classical herbal formula traditionally used to soothe the liver and relieve depression, to strengthen the spleen and regulate metabolism, is clinically used for emotional and metabolic imbalances, but its mechanism in stress-induced MASH remains unclear. Aim of the study Building upon its traditional use in managing stress-related disorders, this study aims to elucidate the therapeutic mechanism by which XYS ameliorates psychosocial stress-induced MASH, thereby providing a mechanistic foundation for its pharmacological application in metabolic disorders with psychosomatic components. Materials and methods A MASH mouse model was established via chronic unpredictable mild stress (CUMS) combined with choline-deficient amino acid-defined high-fat diet (CDAHFD). XYS’s efficacy was evaluated by behavioral assessment (open field test), hepatic histopathology (HE, Oil Red O, Masson/Sirius Red, IHC staining), biochemical analyses (ALT, AST, TG), and ELISA (serum/liver IL-1β, TNF-α). Multi-omics (lipidomics, proteomics, transcriptomics) screened key targets/pathways, validated by rt-qPCR, WB, Co-IP, and IF. Results XYS improved mouse stress status and dose-dependently reduced hepatic lipid deposition, fibrosis, and inflammation. Multi-omics revealed XYS reshaped lipid metabolism by inhibiting the TLR4/IL-1R1/MYD88 axis, upregulating PGC1-α/RXRα, and correcting the reduced binding of RXRα to both PPARα and PGC1-α. Conclusion XYS effectively treats CUMS-induced MASH, likely by inhibiting IL-1R1-mediated inflammation, restoring the reduced binding of RXRα to PPA