Cholestatic and autoimmune liver diseases, bile duct injury, oxidative stress, and therapeutic strategies.

Cholestatic and autoimmune liver diseases, including primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and intrahepatic cholestasis of pregnancy (ICP), represent a heterogeneous group of conditions characterized by impaired bile flow, bile duct injury, and progressive hepatobiliary dysfunction. Oxidative stress has emerged as a critical factor linking bile acid toxicity to inflammation, fibrosis, and loss of biliary epithelium. This review synthesizes current evidence on the pathophysiological interplay between bile duct injury and oxidative stress in PSC, PBC, and ICP, with an emphasis on the role of redox imbalance in disease progression and therapeutic response. Across all three diseases, bile acid accumulation and mitochondrial dysfunction generate reactive oxygen species (ROS) that induce lipid peroxidation, DNA damage, and apoptosis in hepatocytes and cholangiocytes. Biomarkers, including malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and derivatives of reactive oxygen metabolites, correlate with disease severity and prognosis. Current therapeutic strategies target both bile acid metabolism and oxidative stress. Ursodeoxycholic acid (UDCA) enhances glutathione synthesis and reduces lipid peroxidation, while newer agents, such as obeticholic acid (OCA) and fibrates, act via farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) signaling to modulate bile acid homeostasis and redox balance. However, clinical outcomes remain variable, and long-term benefits are not fully established.