Inhibition of Methyltransferase DOT1L alleviates anti-tuberculosis drug-induced liver injury by inhibiting p53-Bax/Bcl-2 pathway.

Anti-tuberculosis drug-induced liver injury (ADLI) is a serious complication of tuberculosis treatment, yet its molecular mechanisms remain poorly understood. Disruptor of telomeric silencing 1-like (DOT1L) is a unique histone methyltransferase that catalyzes monomethylation (me1), dimethylation (me2) and trimethylation (me3) of histone H3 at lysine 79 (H3K79), despite lacking a SET domain. Beyond its methyltransferase activity, DOT1L participates in various biological processes-including the cell cycle, DNA damage response, and gene transcription-both in a methylation-dependent and -independent manner. Notably, dysregulation of DOT1L has been closely associated with the pathogenesis of liver diseases. In this study, we established an ADLI mouse model using a combination of isoniazid, rifampicin, and pyrazinamide, and observed significant upregulation of DOT1L expression in the liver tissues of ADLI mice. Intervention with the specific DOT1L inhibitor SGC0946 markedly alleviated liver injury. Mechanistically, we found that DOT1L catalyzes H3K79 hypermethylation at the p53 gene promoter, leading to activation of the p53-Bax/Bcl-2 apoptosis signaling pathway and subsequent apoptosis of hepatocytes. In contrast, SGC0946 treatment reduced H3K79 methylation levels at the p53 promoter and suppressed the p53-Bax/Bcl-2 pathway, thereby attenuating liver injury. Our findings highlight the importance of DOT1L expression homeostasis in liver physiology and reveal a novel epigenetic mechanism by which DOT1L participates in ADLI progression through transcriptional regulation of p53. These results position DOT1L as a potential therapeutic target for the prevention or treatment of ADLI.