Pachymic Acid Alleviates Non‐Alcoholic Fatty Liver Disease via FGF21 ‐Mediated Inhibition of the p38 MAPK Pathway

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in the liver (hepatic steatosis). Pachymic acid (PAC) has demonstrated potential in alleviating hepatic steatosis in NAFLD. However, the molecular mechanisms by which PAC exerts its effects on NAFLD remain unclear. This study aims to elucidate the molecular pathways through which PAC mitigates hepatic steatosis in NAFLD. A free fatty acid (FFA)-induced hepatic steatosis model was established to assess the regulatory effects of PAC on lipid metabolism. Transcriptome sequencing was performed to explore how PAC influences gene expression in the steatotic HepG2 cells. To confirm the mechanistic role of PAC in hepatic steatosis, we inhibited FGF21 expression in HepG2 cells using nAbFGF21. Finally, a NAFLD mouse model inducted with a high-fat diet (HFD) was established to further examine PAC's therapeutic effects and underlying pharmacological mechanisms in the context of NAFLD. Research findings showed that PAC treatment significantly reduced lipid accumulation and mitigated cellular damage. Transcriptomic analysis revealed a marked enrichment of the MAPK signaling pathway. Further assays confirmed that PAC increased FGF21 and FGFR1 levels in FFA-induced HepG2 cells and reduced the phosphorylation of p38MAPK. Importantly, FGF21 emerged as a critical mediator of PAC's pharmacological effects, as neutralizing FGF21 diminished PAC's ability to inhibit p38MAPK activation. In vivo experiments corroborated PAC's therapeutic effects, showing improvements in lipid metabolism and liver injury in NAFLD. Overall, PAC alleviates hepatic steatosis in NAFLD by enhancing FGF21 expression, activating the FGF21/FGFR1 signaling axis, and inhibiting p38MAPK activation.