Drug-Induced Liver Injury: Mitochondrial Mechanisms, Biomarkers, and Emerging Therapeutic Strategies

Drug-induced liver injury (DILI) remains a major challenge in drug development and clinical pharmacology, contributing significantly to late-stage attrition and regulatory failure. Growing experimental evidence implicates mitochondrial dysfunction as a central mechanism underlying chemically induced hepatotoxicity. This review provides an integrated analysis of mitochondrial pathways involved in DILI, including disruption of oxidative phosphorylation, inhibition of fatty acid β-oxidation, mitochondrial permeability transition, and mitochondrial DNA damage. We synthesize data from in vitro systems, animal models, and human studies to illustrate how diverse xenobiotics converge on mitochondrial targets to trigger hepatocellular injury. Emerging mitochondrial biomarkers, such as glutamate dehydrogenase, circulating mitochondrial DNA, and microRNAs, are discussed in the context of mechanistic relevance and translational utility. In addition, advances in experimental models including humanized mice and liver organoids are evaluated for their predictive value in drug safety assessment. The review further highlights mitochondria-centered intervention strategies as mechanistic tools to validate injury pathways and inform pharmacological risk mitigation. By integrating mitochondrial biology with applied toxicology, this review provides a mechanistic framework to improve early detection, mechanistic understanding, and prevention of drug-induced liver injury during drug development.