Hypolipidemic and Hepatoprotective Effects of 5-(4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy)Pentanoic Acid (TDPPA) on Hyperlipidemic Mice

Introduction: Hyperlipidemia is a prevalent condition that accelerates the development of cardiovascular diseases. Traditional treatments targeting lipid regulation often have limitations, such as hepatotoxicity. This study investigates the dual action of a novel compound, 5-(4-(3-thioxo- 3H-1,2-dithiol-5-yl)phenoxy)pentanoic acid (TDPPA), in reducing lipid levels and protecting the liver. Methods: TDPPA was synthesized and structurally confirmed by 1H-NMR, 13C-NMR, and HRMS. Its lipid-lowering efficacy was first assessed in Triton WR-1339-induced acute hyperlipidemic mice. Mechanistic studies were then conducted in a high-fat emulsion-induced chronic hyperlipidemia model, incorporating histopathological analysis of the liver (H&E and Oil Red O staining). Liver index, serum lipid panels, hepatic function markers, HⁿS content, oxidative stress parameters, and pro-inflammatory cytokines were quantified via ELISA, while the interaction between TDPPA and PPAR-α was evaluated by molecular docking and Western blotting. Results: TDPPA significantly reduced serum triglyceride (TG), total cholesterol (TC), and lowdensity lipoprotein cholesterol (LDL-C) in both acute and chronic models, while increasing highdensity lipoprotein cholesterol (HDL-C). Histology revealed marked reductions in hepatic lipid accumulation and inflammatory infiltration. Biochemical assays showed decreases in AST and ALT, enhanced antioxidant capacity (higher SOD and HⁿS, lower MDA), and suppression of TNF- α, IL-6, and IL-1β. Molecular docking and Western blot analysis indicated that these effects were associated with upregulation of PPAR-α protein expression. Discussion and Conclusion: TDPPA demonstrates potent lipid-lowering, antioxidant, and antiinflammatory activities, likely through a dual mechanism involving PPAR-α activation and HⁿSmediated hepatoprotection. These findings position TDPPA as a promising therapeutic candidate for hyperlipidemia with the benefit of liver protection.