Senescence in HBV-, HCV- and NAFLD- Mediated Hepatocellular Carcinoma and Senotherapeutics: Current Evidence and Future Perspective

SIMPLE SUMMARY: Recent scientific discoveries identify cell senescence as pivotal in hepatocellular cancer (HCC) biology. Specifically, hepatitis B virus (HBV), hepatitis C virus (HCV) and non-alcoholic fatty liver disease (NAFLD) are major risk factors for HCC occurrence and it seems that cell senescence serves as a mediator. Furthermore, senescence is also implicated in HCC therapy resistance. Therefore, understanding and harnessing senescence (via senotherapeutics) seems highly important towards the discovery of new preventative and treatment strategies. Herein, we review the role of cell senescence in HBV-, HCV- and NAFLD- mediated HCC, and also explore the possible place of senotherapeutics in the management of HCC. By shining the spotlight on senescence-mediated HCC, we aim to inspire future research towards this rapidly evolving and highly promising field. ABSTRACT: Cell senescence constitutes a physiological process that serves as protection from malignant transformation of cells. However, recent scientific discoveries also identify cell senescence as pivotal in hepatocellular cancer (HCC) biology. The review herein aimed to accumulate evidence on senescence as a mediator of HCC occurrence in hepatitis B (HBV), C (HCV) virus infections, and non-alcoholic fatty liver disease (NAFLD). In HBV infection, the carcinogenic HBV X protein frequently mutates during chronic infection, and subsequently exhibits different effects on senescence. In HCV infection, senescent non-functional T-cells do not effectively clear pre-malignant hepatocytes. Furthermore, the HCV Core protein inhibits the occurrence of normal stress-induced hepatocyte senescence, allowing damaged cells to maintain their proliferative potential. In NAFLD-mediated HCC, current data point towards the gut microbiome and hepatic stellate cell senescence. Additionally, senescence contributes in the development of resistance in targeted therapies, such as sorafenib. Finally, the promising role of senotherapeutics in HCC was also explored. Overall, although we may still be at a primitive stage in fully unraveling the role of senescence in cancer, it seems that understanding and harnessing senescence may have the potential to revolutionize the way we treat hepatocellular cancer.