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Understanding the mechanistic basis of INH and RIF\u2010induced hepatotoxicity is essential for developing effective preventive and therapeutic strategies. This review provides a comprehensive overview of hepatic metabolism and bioactivation pathways of INH and RIF, highlighting how their co\u2010administration potentiates synergistic hepatotoxic effects. We further explore genetic polymorphisms in drug\u2010metabolizing enzymes and epigenetic modifications, including DNA methylation and histone remodeling, which modulate susceptibility to hepatotoxicity. Special attention is given to the epigenetic regulation of key detoxification enzymes such as cytochrome P450 2E1 (CYP2E1), N\u2010acetyltransferase 2 (NAT2), glutathione S\u2010transferase Mu 1 (GSTM1), glutathione S\u2010transferase (GST) theta 1 (GSTT1), UDP glucuronosyltransferase family 1 member A1 (UGT1A1), and nuclear factor\u2010erythroid 2\u2013related factor 2 (NRF2) pathway. Additionally, we examined immune\u2010mediated mechanisms, including hapten formation, Tool\u2010like receptor\u20104 (TLR4) driven innate immune responses, and human leukocyte antigen (HLA) associated adaptive recognition, which integrated with toxic insults under the dual\u2010hit hypothesis. By elucidating the interplay between metabolism, genetics, epigenetics, and immune pathways, this review highlights emerging insights into the pathogenesis of INH and RIF\u2010induced hepatotoxicity, offering potential avenues for precision risk assessment and hepatoprotective interventions.<\/jats:p>","DOI":"10.1002\/ardp.70204","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T08:23:15Z","timestamp":1772958195000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Review on Isoniazid and Rifampicin\u2010Associated Hepatotoxicity: From Metabolism to Immunity"],"prefix":"10.1002","volume":"359","author":[{"given":"Zahra","family":"Batool","sequence":"first","affiliation":[{"name":"Department of Urology and Institutes for Systems Genetics, Frontiers Science Center for Disease\u2010related Molecular Network, West China Hospital Sichuan University Chengdu 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