CYP2E1 and CYP2D6 in Anti-Tuberculosis Drug-Induced Liver Injury: Mechanisms, Epigenetic Regulation, and Translational Implications.

Tuberculosis (TB) continues to be a significant global health issue, with anti-tuberculosis drug-induced liver injury (ATDILI) representing the most frequent and severe adverse event associated with first-line therapy. Despite extensive investigation, the mechanistic basis of ATDILI remains incompletely understood. Recent evidence underscores the critical role of epigenetic regulation, particularly DNA methylation, in modulating the expression of cytochrome P450 (CYP) enzymes and influencing drug metabolism and hepatotoxicity. This review synthesizes current knowledge on the pharmacoepigenetic mechanisms underlying ATDILI, with a focus on CYP2E1 and CYP2D6 methylation. Evidence reviewed herein suggests that aberrant CYP2E1 methylation may alter isoniazid metabolism, reactive metabolite formation, and oxidative stress, leading to context-dependent hepatocellular injury. The potential involvement of CYP2D6 methylation in ATDILI is examined through pathways related to impaired detoxification and autoimmune responses, particularly in patients with viral coinfections or immune dysregulation. Furthermore, these findings highlight the translational potential of DNA methylation signatures as diagnostic biomarkers and therapeutic targets through epigenome editing. Although current evidence is limited by small, population-specific studies, the integration of multi-omics approaches and artificial intelligence-based modeling could advance early prediction and precision management of ATDILI. A deeper understanding of the epigenetic determinants influencing anti-TB drug safety could facilitate the development of personalized therapeutic strategies and support the overarching objective of TB eradication.