Safflower Polysaccharides Target FXR to Regulate Intestinal Flora and Metabolic Disorders, Affecting FGFR4/FGF15 to Improve Alcoholic Liver Fibrosis in Mice

Chronic alcohol consumption disrupts gut microbiota and metabolic processes, leading to the transfer of microbial toxins from the intestines to the liver and accelerating the progression of alcoholic liver fibrosis (ALF). However, no effective drugs currently exist to treat ALF. Safflower polysaccharide (SPS), a natural compound extracted from safflower, has garnered significant attention in recent years for its potential clinical applications in treating liver-related diseases. However, the efficacy of SPS in improving ALF and its underlying mechanisms remain unclear. Research indicates that SPS alleviates liver injury in ALF mice by modulating inflammation and fibrosis mechanisms through the gut-liver axis and inhibiting hepatic stellate cell activation. SPS promotes the proliferation of beneficial bacteria, improves gut microbiota composition—including Lactobacillus and Bifidobacterium—and alters bile acid pool composition and its metabolites. Notably, the protective effect of SPS in ALF mice is attenuated by FXR inhibition. In vitro experiments confirmed that SPS effectively activates the FXR/FGFR4/FGF15 signaling pathway, counteracting the inhibitory effects of alcohol or specific bile acids on FXR activity. Immunofluorescence and Western blot analyses further confirmed that SPS enhances FXR activity by promoting its expression. These findings reveal a dual mechanism of action for SPS through regulating gut microbiota and bile acid metabolism, providing a theoretical basis for FXR-targeted therapy in ALF and suggesting that the FXR/FGFR4/FGF15 pathway may represent a potential mechanism of action.