Schisandrin A ameliorates obesity and MAFLD through bile acid context-dependent modulation of intestinal FXR signaling.

BACKGROUND: Schisandrin A (Sch A), a major bioactive lignan isolated from Schisandra chinensis, exhibits hepatoprotective and metabolic regulatory activities. However, whether its metabolic effects involve context-dependent regulation of intestinal farnesoid X receptor (FXR) signaling under distinct bile acid environments remains unknown. OBJECTIVE: To investigate how Sch A regulates intestinal FXR to ameliorate obesity and MAFLD. METHODS: DIO and MAFLD mouse models were established separately with Fexaramine (Fex) as a positive control. Therapeutic effects were evaluated through histopathology, biochemistry, metabolic phenotyping, and targeted bile acid metabolomics. Mechanisms were explored using microbiota depletion, fecal microbiota transplantation, intestine-specific Fxr knockout mice, intestinal Camk2d knockdown mice, and target-binding assays. RESULTS: Sch A reduced body weight, improved glucose and lipid metabolism, alleviated hepatic steatosis, and enhanced energy expenditure in both obesity and MAFLD models, with broader effects on selected metabolic endpoints, particularly in DIO mice, compared with Fex. In DIO mice, Sch A reduced bile salt hydrolase-producing Lactobacillus, increased conjugated bile acids, inhibited intestinal FXR signaling to enhance bile acid synthesis and boost energy expenditure. In MAFLD mice, Sch A restored FXR activity in association with FXR engagement, CAMK2D-dependent phosphorylation, and nuclear translocation. CONCLUSION: Sch A ameliorates obesity and MAFLD through bile acid context-dependent regulation of intestinal FXR, supporting further preclinical evaluation of Sch A in metabolic disease models.