CYP4A14-PPARα axis serves as a therapeutic target for ursodeoxycholic acid in ameliorating high-fat diet-induced MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a progressively critical global health concern, with no pharmacological interventions currently approved. Ursodeoxycholic acid (UDCA), an endogenous bile acid utilized in clinical practice, has demonstrated therapeutic potential in treating MASLD. However, the precise mechanisms by which UDCA exerts its hepatoprotective effects in MASLD remain to be fully characterized. We found that UDCA intervention markedly alleviated HFD-induced phenotypes, including hepatic steatosis, inflammation and metabolic disturbances, in high-fat diet (HFD)-fed mice. Mechanistically, UDCA treatment significantly activated hepatic peroxisome proliferator-activated receptor α (PPARα) and Cytochrome P450 family 4 subfamily A member 14 (CYP4A14)-mediated β-fatty acid oxidation. In vitro, treatment with UDCA effectively reduced lipid accumulation and liver enzyme release in AML12 hepatocytes subjected to palmitic acid (PA) and oleic acid (OA) challenge. UDCA administration significantly activated the PPARα-CYP4A14 signaling pathway, however, siRNA-mediated knockdown of these components resulted in a significant reduction of UDCA's protective efficacy in alleviating lipid accumulation in PA/OA-induced cellular models. Additionally, molecular docking and molecular dynamics simulations demonstrated stable interactions between UDCA and CYP4A14, indicating that UDCA may directly regulate CYP4A14 signaling. In conclusion, this study elucidates the CYP4A14-involved PPARα signaling as a novel mechanism by which UDCA exerts its anti-MASLD effects, thereby providing a theoretical foundation for considering UDCA as a potential therapeutic agent for MASLD.