A Metabolic Switch Controlling Liver Cancer Evolution from Senescent NASH Hepatocytes

Hepatocellular carcinoma (HCC), the third most common cancer, originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged primarily by viruses or nonalcoholic steatohepatitis (NASH)1,2. While increasing HCC risk3, NASH also induces TP53-dependent hepatocyte senescence4. How this tumor-suppressive response is activated but eventually bypassed to license HCC progression is unknown. We identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a TP53 target, induced in senescent NASH hepatocytes but downregulated in most human HCCs. Initial FBP1 downregulation in disease-associated hepatocytes, whose accumulation precedes HCC development5, activates AKT to inhibits GSK3 substrate binding, thereby augmenting activation of NRF2 which accelerates FBP1 and TP53 degradation. Intrinsic NRF2 activation and FBP1 loss trigger overlapping transcriptomic responses that suppress senescence, enhance hepatocyte proliferation and metabolism, and enable NRAS- or NASH-induced hepatocarcinogenesis. This AKT-dependent metabolic switch, operative in mice and humans, controls NASH to HCC progression. Our results further suggest that NASH-related hepatocyte senescence is triggered by hypernutrition-induced single strand DNA breaks. Senescence reversal enables HCC progenitor expansion and somatic mutagenesis. Overall design: For HCC induction by hydrodynamic injection, Fbp1?Hepor Nfe2l2Act-Hep mice were intravenously(i.v.) injected with NRASG12V (12.5 µg/ml) and Sleeping Beauty transposase (SB13) (2.5 µg/ml) plasmids diluted in Ringer's solution at 0.1 ml/g body weight in 5-7 seconds.