LAUSR

Simple Summary Cellular identity and function depends on the correct and specific expression of genetic information. Different epigenetic mechanisms including DNA methylation, modifications of histones, and expression of non-coding RNAs control chromatin structure and DNA accessibility to the transcriptional machinery. Alterations of these mechanisms are associated with the development of multiple diseases. The incidence of chronic liver diseases, including hepatocellular carcinoma (HCC), is increasing worldwide. However, the management of those patients is poor due to the late diagnosis of the disease and the absence of effective therapies. Here, we review the epigenetic alterations described in the process of hepatocarcinogenesis, and we discuss the applicability of epigenetic markers as therapeutic targets and liquid biopsy biomarkers for diagnosis. Abstract Research in the last decades has demonstrated the relevance of epigenetics in controlling gene expression to maintain cell homeostasis, and the important role played by epigenome alterations in disease development. Moreover, the reversibility of epigenetic marks can be harnessed as a therapeutic strategy, and epigenetic marks can be used as diagnosis biomarkers. Epigenetic alterations in DNA methylation, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) expression have been associated with the process of hepatocarcinogenesis. Here, we summarize epigenetic alterations involved in the pathogenesis of chronic liver disease (CLD), particularly focusing on DNA methylation. We also discuss their utility as epigenetic biomarkers in liquid biopsy for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Finally, we discuss the potential of epigenetic therapeutic strategies for HCC treatment.