Mechanistic insights into atorvastatin-induced hepatotoxicity: molecular pathways, clinical relevance, and strategies for safer personalized therapy

Atorvastatin, a chemically defined HMG-CoA reductase inhibitor, is widely prescribed for hyperlipidemia and cardiovascular disease prevention. However, it has been implicated in hepatotoxic effects ranging from transient transaminase elevations to rare but severe liver injury. This review critically examines the molecular and biochemical mechanisms underlying atorvastatin-induced hepatotoxicity, emphasizing translational relevance and human health risk assessment. A structured literature search (2000-2025) integrated evidence from clinical reports, experimental models, and pharmacogenomic studies. Key pathways analyzed included mitochondrial dysfunction, oxidative stress, bile acid dysregulation, and inflammatory signaling, with special attention to genetic polymorphisms (SLCO1B1, CYP3A4, UGT1A1) and drug-drug interactions. Atorvastatin-induced hepatotoxicity results from interconnected molecular events. Mitochondrial dysfunction impairs electron transport chain activity, causing ATP depletion and excessive ROS production. Oxidative stress drives lipid peroxidation, protein modification, and DNA injury, while inhibition of bile acid transporters (BSEP, NTCP, MRP2) promotes cholestatic damage. ROS and bile acid accumulation activate Kupffer cells and the NLRP3 inflammasome, amplifying inflammatory cascades (e.g., TNF-α, IL-1β). Pharmacogenomic variations in SLCO1B1, CYP3A4/5, and UGT1A1 modulate atorvastatin disposition and susceptibility, contributing to idiosyncratic injury. Drug-drug interactions further intensify hepatotoxic risk. Mechanistic insights support preventive strategies such as genotype-guided dosing, structured liver function monitoring, and adjunctive therapies targeting oxidative stress, mitochondrial stabilization, or bile acid homeostasis. Defining these mechanistic pathways provides a framework for integrating pharmacogenomic data and mechanistic biomarkers into clinical practice, enabling safer, more personalized statin therapy and improving risk stratification in drug-induced liver injury.