Hepatic fibrosis is a major cause of mortality in patients with non-alcoholic steatohepatitis (NASH). Hepatic fibrosis also plays a major role in the development of hepatocellular carcinoma (HCC, which is a second leading cause of cancer mortality world-wide. Hepatic stellate cells (HSCs) that generate hepatic fibrosis are activated by liver injury, but the mechanism of their activation is not fully understood. Upon activation HSCs start expressing genes such as alpha-smooth muscle actin (aSMA) and collagen type 1a1 (Col1a1), which are markers of hepatic fibrosis. Upon activation HSCs become highly glycolytic and consequently produce high level of lactate. Lactate has been suggested to play a role in regulating gene expression upon HSCs activation, but the mechanism remains elusive. We found that high glycolysis and lactate production in activated HSCs is largely due to the induction of hexokinase 2 (HK2) expression. Our results show that HK2 is required for the activation of HSCs and liver fibrosis. Interestingly, we found that lactate produced, because of HK2 expression, induces histone lactylation, which is required for gene expression in activated HSCs. In the absence of HK2 the induction of gene expression is impaired in HSCs, but lactate could override the effect of HK2 deletion on gene expression. We also found that HK2 deletion in hepatocytes attenuates NASH-induced hepatocarcinogenesis. Therefore, our results suggest that targeting HK2 could be therapeutic for both liver fibrosis and NASH-induced HCC. In this grant application we will further validate the role of HK2 in liver fibrosis and how it affects NASH-induced HCC. We will employ a mouse model of NASH-induced HCC in which there is extensive fibrosis. We will use these mice to study the role of HK2 in the interplay between liver fibrosis and HCC. Finally, as a proof of concept, we will verify if systemic HK2 deletion, which does not elicit adverse physiological consequences, could inhibit both fibrosis and HCC in a mouse model of NASH-induced HCC.