The extent of liver injury determines hepatocyte fate toward senescence or cancer

Induction of hepatocyte senescence is known to inhibit hepatocellular carcinoma (HCC). Until now, it has not been clear how the degree of liver injury dictates hepatocyte senescence and carcinogenesis. In this study, we investigated whether the severity of injury determines cell fate decisions between hepatocyte senescence and carcinogenesis. After testing of different degrees of liver injury, we found that hepatocyte senescence is strongly induced in the setting of severe acute liver injury. Longer-term, moderate liver injury did not result into hepatocyte senescence, but instead led to a significant incidence of HCC. In addition, carcinogenesis was significantly reduced by the induction of severe acute injury after chronic moderate liver injury. We conclude that severe acute liver injury leads to hepatocyte senescence along with a low incidence of HCC, whereas chronic moderate injury allows hepatocytes to proliferate rather than to enter into senescence, and correlates with a high incidence of HCC. This study improves our understanding in hepatocyte cell fate decisions and suggests a potential clinical strategy to induce senescence to treat HCC. moderate chronic liver injury for 8 weeks or 12 weeks or moderate chronic liver injury for 8 weeks plus severe liver injury 4 weeks