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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 (\n                    <jats:italic>CYP<\/jats:italic>\n                    ) enzymes and influencing drug metabolism and hepatotoxicity. This review synthesizes current knowledge on the pharmacoepigenetic mechanisms underlying ATDILI, with a focus on\n                    <jats:italic>CYP2E1<\/jats:italic>\n                    and\n                    <jats:italic>CYP2D6<\/jats:italic>\n                    methylation. Evidence reviewed herein suggests that aberrant\n                    <jats:italic>CYP2E1<\/jats:italic>\n                    methylation may alter isoniazid metabolism, reactive metabolite formation, and oxidative stress, leading to context\u2010dependent hepatocellular injury. The potential involvement of\n                    <jats:italic>CYP2D6<\/jats:italic>\n                    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\u2010specific studies, the integration of multi\u2010omics approaches and artificial intelligence\u2010based modeling could advance early prediction and precision management of ATDILI. A deeper understanding of the epigenetic determinants influencing anti\u2010TB drug safety could facilitate the development of personalized therapeutic strategies and support the overarching objective of TB eradication.\n                  <\/jats:p>","DOI":"10.1111\/cts.70628","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T02:53:56Z","timestamp":1780973636000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>CYP2E1<\/scp>\n                    and\n                    <scp>CYP2D6<\/scp>\n                    in Anti\u2010Tuberculosis Drug\u2010Induced Liver Injury: Mechanisms, Epigenetic Regulation, and Translational Implications"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4355-8573","authenticated-orcid":false,"given":"Pathida","family":"Prakongsup","sequence":"first","affiliation":[{"name":"Master of Science Program in Biopharmaceutical Sciences, Department of Biochemistry, Faculty of Pharmacy Mahidol University  Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1132-7442","authenticated-orcid":false,"given":"Wanvisa","family":"Udomsinprasert","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy Mahidol University  Bangkok Thailand"},{"name":"Biomarker and Epigenetic Science for Targeted Therapeutics (BEST) Research Center, Faculty of Pharmacy Mahidol University  Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.TNMI7\u20100032\u20102016"},{"key":"e_1_2_11_3_1","volume-title":"Global Tuberculosis Report 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