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BackgroundAnti-tuberculosis drug-induced liver injury (ADLI) limits the treatment of tuberculosis. The mechanisms underlying ADLI are unclear and there are no effective preventative measures to avoid this complication. MethodsIn this stuy, the protein contents of EZH2, Nrf2, NQO1 and HO-1 were detected by ELISA kit, while those of EZH2 and Nrf2 were determined by Western blot. The Chip experiment was used to detect the level of H3K27me3 in the Nrf2 promoter region.The liver were analyzed histopathologically in vivo using hematoxylin and eosin staining.ResultsHere we developed a murine model of ADLI that recapitulates liver injury in the human disease. Using this model, we investigated the potential involvement of the enhancer of zeste homolog 2 methyltransferase (EZH2), a histone methyltransferase which inhibits the transcriptional activation of the Nrf2-ARE oxidative stress pathway. Compared to controls, mice livers with ADLI showed decreased expression of EZH2 together with reduced H3K27me3 marks in the Nrf2 promoter. This was accompanied by increased expression of Nrf2 and its target genes NQO1 and HO-1. Liver injury in the mice with ADLI could be alleviated to an extent by in vivo delivery of siRNAs targeting EZH2, which further downregulated EZH2 expression and H3K27me3 levels in the Nrf2 promoter along with accompanying increases in Nrf2, NQO1 and HO-1 expression. ConclusionsTherefore, inhibiting EZH2 likely reduced liver damage in ADLI by enhancing this key anti-oxidative stress pathway. Our results establish a role for EZH2 in a mouse model of ADLI and furthermore provides valuable mechanistic insights into the development of ADLI pathology. |
