Hepatitis B virus–induced hepatocellular carcinoma: HBx-associated epigenetic mechanisms and therapeutic opportunities

Chronic hepatitis B virus (HBV) infection is a major etiological factor in the development of hepatocellular carcinoma (HCC), a cancer that causes a large number of cancer-related deaths around the world. Although antiviral treatments are effective, the risk of HCC remains because studies using advanced sequencing have shown that liver cells still carry integrated viral DNA, experience ongoing inflammation, and undergo lasting changes in epigenetic regulation. HBV maintains its genome in liver cells as a chromatin-like cccDNA structure, and with the help of the HBx protein, it manipulates the cell’s chromatin machinery to support viral gene expression and disrupt normal control of enhancers, DNA methylation, and Polycomb regulation. These alterations enhance transcriptional plasticity and, in the context of chronic liver injury and additional somatic mutations, may contribute to malignant transformation. This review highlights recent mechanistic studies that have suggested a pathway linking HBV persistence to chromatin dysfunction. Further, it outlines an emerging therapeutic opportunity with chromatin-directed drugs, as well as rational combinations of these drugs with immunotherapy for HBV-related HCC.