Homo sapiens Epigenomics

Chronic hepatitis B virus (HBV) infection is the main etiology of liver fibrosis (LF), leading to cirrhosis and liver tumors. DNA methylation caused by HBV protein changes the liver microenvironment and activates hepatic stellate cells, which is an important mechanism of liver fibrosis. However, the exact mechanism remains unclear.DNA methyltransferase 3A (DNMT3A) is a major enzyme that promotes DNA methylation. HBV infection promotes the expression of DNMT3A.We used lentivirus to construct HepG2 cells overexpressing DNMT3A.Then the conditioned medium of the cells was cocultured with hepatic stellate cells (LX-2), and it was found that LX-2 cells were activated.To explore the specific mechanisms, DNMT3A overexpression HepG2 cells were performed to multi-omics analysis.It revealed that DNMT3A methylated the promoter region of UNC13D and inhibited its expression.The decrease of UNC13D expression promoted the activation of STING signaling pathway.Therefore, our study reveals a novel mechanism by which hepatocytes change the liver microenvironment to promote the activation of HSCs, and the results highlight the potential of targeting DNMT3A as a promising therapeutic strategy in reversing LF.