Unlocking the Hepatoprotective Potential of Urolithin A in High-Fat Diet-Induced MASLD: Integrated Role of Oxidative Stress, Inflammation, FXR/PPAR-α, and Fibrotic Pathway.

"Metabolic dysfunction-associated steatotic liver disease" (MASLD) is marked by hepatic steatosis, oxidative stress, inflammation, and fibrosis. Urolithin A (Uro A), a metabolite of ellagitannins, exhibits anti-inflammatory, antioxidant, and metabolic regulatory activities. This work examined the preventive benefits of Uro A against high-fat diet (HFD)-induced MASLD in rats and elucidated the underlying mechanisms. Four experimental groups of rats were established: control, Uro A, HFD, and HFD-Uro A. MASLD was induced by 12 weeks of HFD feeding. Uro A (2.5 mg/kg, intraperitoneally) was administered four times weekly. Metabolic indices, lipid profile, liver transaminases, oxidative stress markers, inflammatory mediators, fibrogenic markers, and hepatic farnesoid X receptor (FXR) and peroxisomal proliferator-activated receptor (PPAR)-α gene expression were evaluated. Histopathological and immunohistochemical analyses were performed. HFD significantly increased body weight, adiposity, hepatic index, transaminases, dyslipidemia, oxidative stress, inflammatory cytokines, and fibrotic markers, while downregulating FXR and PPAR-α expression. Histopathology revealed steatosis, inflammatory infiltration, and increased expression of tumor necrosis factor alpha (TNF-α), glial fibrillary acidic protein (GFAP), and Bax. Uro A markedly ameliorated metabolic, biochemical, and molecular alterations, with evident histological improvement. These findings demonstrate that Uro A exerts hepatoprotective effects against HFD-induced MASLD through integrated modulation of oxidative stress, inflammation, fibrosis, and FXR/PPAR-α pathway, bolstering its prospects as a multi-target therapeutic option for MASLD.