Optimizing clofibrate with eugenol contributes a novel hypolipidemic agent with minimal liver injury.

It is well-established that clofibrate (CF)-induced hepatotoxicity involves oxidative stress and inflammatory responses. To address this issue, we employed a molecular hybridization strategy to optimize the CF structure, aiming to develop compounds with improved lipid-lowering efficacy, antioxidant capacity, and anti-inflammatory properties while minimizing hepatotoxicity risk. The designed hybrid molecule, eugenol-clofibrate (CF-Eugenol), was synthesized by replacing the ethoxy group of CF with eugenol. In vitro and in vivo evaluations demonstrated that CF-Eugenol exhibits high binding affinity for PPAR-α and effectively reduces serum triglyceride (TG) and total cholesterol (TC) levels in hyperlipidemic mice. Notably, CF-Eugenol significantly mitigates liver injury, as evidenced by reduced liver coefficient, decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and improved liver tissue pathology (e.g., reduced cell degeneration, necrosis, and swelling). Mechanistically, CF-Eugenol suppresses inflammatory responses by downregulating pro-inflammatory cytokines (TNF-α and IL-6) and alleviates oxidative stress through enhanced superoxide dismutase (SOD) activity and glutathione (GSH) levels, accompanied by reduced malondialdehyde (MDA) accumulation. Further analysis revealed that these effects are mediated via the activation of the Nrf2/HO-1 pathway. Collectively, CF-Eugenol demonstrates superior lipid-lowering activity with reduced hepatotoxicity, potentially through its dual anti-inflammatory and antioxidant mechanisms driven by Nrf2/HO-1 pathway activation. This hybrid strategy offers a promising approach for designing safer lipid-modulating agents.