Tet2 Protects Against Isoniazid-Induced Hepatotoxicity via Regulating Autophagy

Hepatotoxicity is a significant clinical challenge that severely limits the therapeutic application of isoniazid (INH), a globally recommended first-line anti-tuberculosis (TB) drug. Despite its essential role in TB treatment, the underlying mechanisms of INH-induced liver injury remain incompletely understood. This study investigates the role of Ten-eleven translocation 2 (Tet2) in INH-induced 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- and time-dependent reduction manner following INH exposure. In vitro, Tet2 silencing exacerbated INH-induced autophagy and hepatotoxicity. Consistently, Tet2 conventional knockout (Tet2KO) mice exhibited more severe liver injury compared to their matched wild-type siblings under INH administration, accompanied by significantly increased hepatic LC3II and decreased P62 expression. Notably, vitamin C, a known cofactor that enhances Tet-mediated DNA demethylation, not only restored Tet2 expression and function but also attenuated INH-triggered autophagy and concomitantly alleviated liver injury in INH-treated mice. In conclusion, our findings establish Tet2 as a crucial protective factor against INH-induced 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.