Paeoniflorin Alleviates Metabolic Dysfunction-Associated Steatotic Liver Disease by Inhibiting Hepatic Lipogenesis and Inflammation

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious chronic liver disease involving metabolic dysfunction of multiple organs. Paeoniflorin (PF) has been found to improve high-fat diet (HFD)-induced liver fat accumulation. Here, we will reveal the molecular mechanism by which PF improves MASLD. C57BL/6J mice were fed with HFD to establish a classic diet-induced MASLD model followed by PF administration. The effects of PF on endogenous metabolites, gut microbiota, gene, and protein levels in liver tissues with MASLD were investigated using Bulk RNA-seq, broadly targeted metabolomics, 16 S rRNA sequencing, western blot and immunohistochemistry. PF significantly inhibited HFD-induced increases in serum levels of TC, TG, ALT, and AST, and markedly reduced lipid accumulation in liver tissue. Mechanistically, PF significantly suppressed the expression levels of lipid synthesis and inflammation signaling-related targets in liver tissue, such as IL-17 A, CLCX10, MMP13, HIF-1, FoxO, FASN, SREBP1, and ACC1. Furthermore, PF markedly altered the gut microbiota profile in mice with MASLD, and these alterations were closely associated with distinct endogenous metabolites in the liver tissue. Current findings demonstrate that PF ameliorates MASLD by regulating hepatic lipid metabolism, inflammation and intestinal microbial signaling.