Tet2 Protects Against Isoniazid-Induced Hepatotoxicity via Regulating Autophagy
Decheng Wang1,2,3,4, Shujun Wang1,2,3, Zhu Jin5
1Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China.
Summary
Ten-eleven translocation 2 (Tet2) protects against isoniazid (INH)-induced liver injury by regulating autophagy. Enhancing Tet2, potentially with vitamin C, may mitigate liver damage in tuberculosis patients.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Isoniazid (INH) is a vital first-line tuberculosis drug, but its use is limited by hepatotoxicity.
- The precise mechanisms underlying INH-induced liver injury are not fully understood.
- Autophagy plays a complex role in cellular responses to drug-induced injury.
Purpose of the Study:
- To investigate the role of Ten-eleven translocation 2 (Tet2) in isoniazid-induced hepatotoxicity.
- To elucidate Tet2's regulatory mechanism on autophagy during hepatocellular injury.
- To explore potential therapeutic strategies targeting Tet2 for mitigating INH-induced liver damage.
Main Methods:
- In vitro studies involving Tet2 silencing in hepatocytes exposed to INH.
- In vivo studies using Tet2 conventional knockout (Tet2KO) mice treated with INH.
- Assessment of autophagy markers (LC3II, P62) and liver injury indicators.
- Evaluation of vitamin C supplementation effects on Tet2 expression, autophagy, and liver injury.
Main Results:
- INH administration significantly enhanced hepatocyte autophagy and reduced Tet2 expression in a dose- and time-dependent manner.
- Tet2 silencing or knockout exacerbated INH-induced autophagy and liver injury.
- Vitamin C supplementation restored Tet2 expression, attenuated INH-induced autophagy, and alleviated liver injury.
Conclusions:
- Tet2 acts as a critical protective factor against INH-induced liver injury by modulating autophagy.
- Tet2 deficiency exacerbates INH-induced hepatotoxicity.
- Enhancing Tet2 expression, potentially via vitamin C, offers a promising therapeutic strategy to reduce INH-related liver damage in tuberculosis patients.
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