Hepatocellular carcinoma (HCC) remains one of the most prevalent malignant diseases worldwide, and the majority of cases are related to hepatitis B virus (HBV) infection. Interactions between the HBV-encoded X (HBx) protein and host factors are known to play major roles in the onset and progression of HBV-related HCC. These dynamic molecular mechanisms are extremely complex and lead to prominent changes in the host genetic and epigenetic architecture. This review summarizes the current knowledge about HBx-induced epigenetic changes, including aberrations in DNA methylation, histone modifications, and microRNA expression, and their roles in HBV-infected liver cells and HBV-related HCC. Moreover, the HBx-mediated epigenetic control of HBV covalently closed circular DNA (cccDNA) is also discussed. Although this field of study is relatively new, the accumulated evidence has indicated that the epigenetic events induced by HBx play important roles in the development of HBV-related HCC. Ongoing research will help to identify practical applications of the HBV-related epigenetic signatures as biomarkers for early HCC detection or as potential targets to prevent and treat HBV-related HCC.
