Abstract
Simple SummaryRecent 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.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.
Highlights
When Hayflick and Moorhead first described cell senescence in 1961 [1], their findings were received with skepticism
The scientific community acknowledges cell senescence as pivotal in cancer biology and aging research, whereas an emerging new field, known as senotherapeutics, aims to create senescence-modulating agents that affect the course of age-related diseases, such as cancer [4]
Recent scientific advances indicate the importance of senescence in hepatocellular carcinoma (HCC) [5,6], which represents a major cause of mortality worldwide, with a substantial societal and economic burden
Summary
When Hayflick and Moorhead first described cell senescence in 1961 [1], their findings were received with skepticism. Their manuscript was initially rejected [2] and decades passed before the wide acceptance of this concept [3]. Patients are often diagnosed at an advanced stage, which requires systemic treatment. In this patient subgroup, the concept of targeted therapies has stimulated substantial research, with promising drugs being introduced in the period between 2017–2020 [8]. We aimed to review the role of cell senescence in HBV-, HCV- and NAFLD- mediated HCC, as well as to explore the possible place of senotherapeutics in the management of HCC
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