Veratric acid ameliorates metabolic-dysfunction-associated fatty liver disease via targeting PPARG

Metabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most common metabolic syndromes worldwide. Its pathogenesis is multifactorial, involving disruptions in lipid metabolism, insulin resistance, chronic inflammation, and mitochondrial dysfunction. Veratric acid (VA), a naturally occurring phenolic compound, is known for its antioxidant and anti-inflammatory properties; however, its therapeutic potential and underlying mechanisms in the context of MAFLD remain largely uncharacterized. This study aimed to investigate the protective effects and underlying mechanisms of VA in a high-fat diet induced mouse model of MAFLD. In this study, C57BL/6J mice were fed an HFD with or without VA supplementation. Metabolic phenotypes, hepatic steatosis, and serum biochemical parameters were evaluated. In vitro experiments were conducted in HepG2 cells to assess lipid accumulation, mitochondrial function, oxidative stress, and gene expression. Network pharmacology, molecular docking, CETSA, and DARTS assays were employed to identify potential targets. The results demonstrated that VA significantly alleviated HFD-induced weight gain, adipose tissue accumulation, and hepatic steatosis. VA also improved glucose homeostasis, reduced serum lipid levels, and ameliorated liver injury. Mechanistically, VA modulated lipid metabolism by enhancing fatty acid β-oxidation and lipolysis. Network pharmacology, molecular docking, and biochemical validation further identified peroxisome proliferator-activated receptor gamma (PPARG) as a key target of VA. VA stabilized the PPARG protein, thereby promoting lipid metabolic reprogramming. These findings provide new insights into the bioactivity of VA and suggest its potential as a natural therapeutic agent for MAFLD.