Elucidating the Mechanism of Modified Yiguanjian against Anti-Tuberculosis Drug-Induced Liver Injury via Integrated Pharmacology and Metabolomics.

Abstract

This study aimed to investigate the therapeutic effects and molecular mechanisms of Modified Yiguanjian (MYGJ) in treating anti-tuberculosis drug-induced liver injury (ATB-DILI). ATB-DILI is a serious side effect of TB treatment, often leading to liver damage, drug resistance, or failure. The research integrated serum pharmacochemistry, network pharmacology, and metabolomics to uncover MYGJ's hepatoprotective mechanisms. Using ultra-high-performance liquid chromatography coupled with quadrupole-electrostatic field orbitrap mass spectrometry, the study identified 11 prototype compounds of MYGJ in blood serum, including Apigenin and Lonicerin. The ATB-DILI mouse model induced by isoniazid, rifampicin, and pyrazinamide showed MYGJ's effectiveness in reducing liver enzyme levels (alanine aminotransferase, aspartic transaminase, and alkaline phosphatase), improving histopathology, and lowering pro-inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β, and IL-6). Network pharmacology identified 128 shared targets, including key molecules like TP53 and AKT1, and suggested tyrosine and purine metabolism as critical pathways. Metabolomics identified 95 altered metabolites, with MYGJ reversing 38 of them. Molecular docking confirmed strong binding between MYGJ compounds and targets like adenosine deaminase and myeloperoxidase. Overall, MYGJ alleviated ATB-DILI through multi-target, multi-pathway actions, demonstrating its potential for liver protection in clinical settings.