Pioglitazone protects against thioacetamide-induced liver fibrosis via AMPK-mediated inhibition of the TGF-β/Smad fibrotic cascade.

Hepatic fibrosis is a progressive liver disorder driven largely by inflammation and oxidative stress. AMP-activated protein kinase (AMPK) plays a pivotal role in regulating hepatic fibrogenesis and represents a promising therapeutic target. Therefore, this study aimed to investigate the hepatoprotective effects of pioglitazone (PIO) and to evaluate whether AMPK activation contributes to its protective actions against thioacetamide (TAA)-induced hepatic injury and fibrosis. Liver injury was induced by intraperitoneal administration of TAA (150 mg/kg, twice weekly) for 9 weeks. During the last 3 weeks, mice received PIO (3 mg/kg/day, orally). Hepatic injury and fibrosis were assessed using biochemical, histopathological, and molecular analyses. PIO treatment significantly attenuated TAA-induced hepatic injury and fibrosis, as demonstrated by improved liver histology, reduced plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels and gamma-glutamyl transferase (GGT) activity, restoration of plasma albumin, and decreased α-smooth muscle actin (α-SMA) expression. These beneficial effects were associated with increased hepatic p-AMPK expression and reduced oxidative stress, evidenced by decreased malondialdehyde (MDA) and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) levels and restoration of reduced glutathione (GSH) content, as well as suppression of the transforming growth factor-β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) signaling pathway. PIO mitigates TAA-induced hepatic fibrosis, potentially through AMPK activation and subsequent suppression of the TGF-β/Smad signaling pathway, highlighting its potential as a promising antifibrotic agent.