Synthesis and Hepatotoxicity Evaluation of Paeonol Clofibrate.

Clofibrate (CF) is an effective lipid-lowering drug, but its clinical use is restricted by hepatotoxicity. Molecular hybridization with paeonol may improve hepatic safety while preserving efficacy. To synthesize CF-Paeonol and compare its lipid-lowering activity and hepatic safety with CF. CF-Paeonol was prepared by esterifying clofibric acid with paeonol. Its lipid-lowering activity was assessed in Triton WR-1339-induced hyperlipidemic mice, while hepatic safety was evaluated after 30 days of administration in normal mice. Plasma lipids, liver function, bile acids, oxidative stress, inflammation, histopathology, molecular docking, and hepatic YY1/FXR expression were examined. CF-Paeonol dose-dependently reduced triglycerides and total cholesterol. At the high dose, levels decreased by 30.51% and 33.78%, respectively, versus the model group, while the equimolar dose showed efficacy comparable to CF. Compared with CF, CF-Paeonol significantly lowered AST and ALT and reduced the liver histopathological score from 11 to 3. It also improved bile acid, oxidative stress, and inflammatory indices without obvious pathological changes in other organs. Docking predicted interactions with PPAR-α and YY1, and Western blot showed decreased YY1 and increased FXR expression. CF-Paeonol retained lipid-lowering activity with less hepatic injury than CF, warranting further pharmacokinetic, metabolic, and causal mechanistic studies for confirmation.