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Despite its essential role in TB treatment, the underlying mechanisms of INH\u2010induced liver injury remain incompletely understood. This study investigates the role of Ten\u2010eleven translocation 2 (Tet2) in INH\u2010induced hepatotoxicity and elucidates its regulatory mechanism on autophagy during hepatocellular injury. The results showed that INH administration significantly enhanced hepatocyte autophagy, as evidenced by elevated LC3II and decreased P62 levels. Tet2 expression exhibited dose\u2010 and time\u2010dependent reduction manner following INH exposure. In\u00a0vitro, Tet2 silencing exacerbated INH\u2010induced autophagy and hepatotoxicity. Consistently, Tet2 conventional knockout (Tet2KO) mice exhibited more severe liver injury compared to their matched wild\u2010type siblings under INH administration, accompanied by significantly increased hepatic LC3II and decreased P62 expression. Notably, vitamin C, a known cofactor that enhances Tet\u2010mediated DNA demethylation, not only restored Tet2 expression and function but also attenuated INH\u2010triggered autophagy and concomitantly alleviated liver injury in INH\u2010treated mice. In conclusion, our findings establish Tet2 as a crucial protective factor against INH\u2010induced liver injury by modulating autophagy. Enhancement of Tet2 expression, particularly through vitamin C supplementation, presents a promising strategy for mitigating hepatotoxicity in TB patients receiving INH therapy.<\/jats:p>","DOI":"10.1096\/fj.202500245r","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T15:10:03Z","timestamp":1764688203000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tet2 Protects Against Isoniazid\u2010Induced Hepatotoxicity via Regulating Autophagy"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1742-7460","authenticated-orcid":false,"given":"Decheng","family":"Wang","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy China Three Gorges University  Yichang China"},{"name":"College of Basic Medical Sciences China Three Gorges University  Yichang China"},{"name":"Yichang Key Laboratory of Infection 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