Abstract

Chronic metabolic diseases-particularly type 2 diabetes mellitus (T2DM) and the metabolic syndrome-are major 
drivers of contemporary liver morbidity, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), 
fibrosis and cirrhosis. Hepatotoxicity in this context is not a single-pathway event but the outcome of sustained 
metabolic overload, maladaptive immune activation, and persistent oxidative stress that together create 
hepatocellular injury, organelle dysfunction, and maladaptive remodeling. This review synthesizes current 
mechanistic understanding of how hyperglycemia and insulin resistance perturb hepatocyte metabolism, how 
innate and adaptive immune responses amplify tissue damage, and how oxidative stress both mediates and 
perpetuates injury through mitochondrial dysfunction, lipid peroxidation, and disruption of antioxidant pathways 
(e.g., Nrf2). We discuss the role of cytochrome P450 (CYP) enzymes and xenobiotic handling in modifying 
susceptibility to drug-induced liver injury (DILI) in patients with metabolic disease, summarize emerging 
biomarkers 
and 
mechanistic 
readouts, 
and highlight therapeutic strategies targeting the 
metabolic–immune–oxidative axis. Recognizing the interconnectedness of these processes is essential to improving 
diagnosis, stratifying risk for hepatotoxic reactions, and developing targeted interventions for liver protection in 
people with chronic metabolic disease.