Ellagic Acid Attenuates CCl₄-Induced Hepatic Fibrosis and Is Associated with Changes in PI3K/AKT- and EMT-Related...

Hepatic fibrosis is characterized by excessive extracellular matrix deposition and progressive impairment of liver structure and function. Ellagic acid (EA) has been reported to have antioxidant and anti-inflammatory properties, but its role in hepatic fibrosis remains incompletely understood. A CCl₄-induced mouse model of hepatic fibrosis was established. EA was administered by oral gavage at 30, 60, or 120 mg/kg; colchicine was used as a positive control. Histopathological changes and collagen deposition were assessed using hematoxylin and eosin and Sirius Red staining, respectively. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin-6 (IL-6), and interleukin-10 (IL-10) concentrations, as well as hepatic malondialdehyde (MDA) and hydroxyproline (Hyp) contents and total superoxide dismutase (T-SOD) activity, were determined. Immunohistochemistry and Western blotting were used to assess fibrosis-associated, EMT-associated, and PI3K/AKT-related proteins. Network pharmacology analysis was performed to identify candidate targets and pathways. EA treatment ameliorated histopathological injury and collagen deposition in CCl₄-treated mice. EA, particularly at the high dose, reduced serum ALT and AST activities and hepatic MDA and Hyp contents while increasing hepatic T-SOD activity. EA treatment was also associated with lower serum IL-6 and higher IL-10 concentrations. In the EA-H group, α-SMA and collagen I (COL1A1) immunoreactivity were reduced; the abundance of N-cadherin, PI3K, and AKT was lower; and E-cadherin expression was higher. Network pharmacology identified PI3K/AKT-related signaling as a candidate pathway associated with the anti-fibrotic effects of EA. EA attenuated CCl₄-induced hepatic fibrosis and was associated with lower oxidative stress, inflammation, and HSC activation. Direct PI3K/AKT inhibition was not established.