Oxidative Stress in Drug-Induced Liver Injury: Mechanistic Pathways and Modifying Factors
Drug-induced liver injury (DILI) is a leading cause of acute liver failure and a major barrier in drug development and clinical therapeutics. Among the diverse mechanisms implicated in DILI, oxidative stress plays a central role in initiating and propagating hepatocellular damage. Oxidative stress results from an imbalance between the generation of reactive oxygen species (ROS) and the capacity of antioxidant defenses, leading to macromolecular damage, mitochondrial dysfunction, and cell death. A wide range of drugs, including acetaminophen, antibiotics, antiepileptics, and anticancer agents, induce oxidative stress through metabolic activation, redox cycling, and disruption of mitochondrial electron transport. Importantly, individual susceptibility to oxidative damage is influenced by genetic polymorphisms, age, sex, nutritional status, co-medications, and underlying liver disease. Additionally, sex hormones, gut microbiota composition, and environmental exposures modify redox pathways and DILI risk. Understanding how oxidative stress integrates with immune responses, inflammation, and cell death pathways provides insight into mechanisms of liver injury and suggests therapeutic targets. This review synthesizes current knowledge of oxidative stress in DILI pathogenesis, highlights key modifying factors, and discusses potential antioxidant-based interventions for the prevention and mitigation of liver injury.