Metabolic dysfunction-associated steatohepatitis (MASH) is known to increase the risk of hepatocellular carcinoma (HCC), yet also triggers hepatocyte senescence (a tumour-suppressive cell state). New research shows that the gluconeogenic enzyme fructose-1,6-bisphophatase (FBP1) serves as a key control point in the switch from MASH to HCC. “Since senescence describes a non-dividing cell state associated with tumor suppression I found the phenomenon of MASH-associated senescence paradoxical and became interested in solving this conundrum,” explains lead author Michael Karin.

More research is planned to further investigate the development of MASH and HCC and determine whether this process can be targeted therapeutically. “We plan to take this forward by studying how MASH-inducing diets cause hepatocyte DNA damage and whether the activation of TP53 and the upregulation of FBP1 account for selective insulin resistance, which frequently accompanies MASH. We are also interested in finding out whether switching DNA-damage-induced senescence to DNA-damage-induced cell death would result in the attenuation of HCC development.”