A hypothetical model depicting cross-talk between activation of inflammatory pathways and epigenome deregulation during liver tumor development. Different components of the inflammatory response (including transient and stable modifications such as activation of inflammatory pathways nuclear factor (NF)-κB and JAK/STAT) may induce changes in epigenetic machineries (including DNA methylation, histone modifications and non-coding RNAs), resulting in an 'epigenetic switch' that resets the long-term memory system in hepatocytes. The epigenetic switch in turn may contribute to a persistent inflammatory response through altered gene expression states and a positive feedback loop to exacerbate a chronic state of inflammation. In addition, the deregulated epigenome may maintain an altered transcriptional program that promotes proliferation and oncogenic transformation. This interdependent and self-reinforcing cross-talk between inflammation and the epigenome maintains and amplifies inflammatory signals, resulting in a series of events culminating in the development of liver cancer. The epigenetic switch may also be activated in hepatic or liver progenitor cells whose proliferation is stimulated during liver regeneration and repair. Therefore, an inflammatory microenvironment and an epigenetic switch in response to different environmental factors can directly promote activation of liver progenitor cells and their oncogenic transformation. DNMT, DNA methyl transferase.