Non-alcoholic steatohepatitis (NASH) is characterized by liver steatosis, hepatocellular ballooning, and lobular inflammation with or without perisinusoidal fibrosis which collectively promotes cirrhosis and hepatocellular carcinoma (HCC). AMPK can inhibit both NASH and HCC through phosphorylation of acetyl-CoA carboxylase (ACC) and subsequent reductions in denovo lipogenesis (Fullerton et al Nat Med 2013 and Lally et al. Cell Met 2019). In this presentation we will discuss new upstream regulators and downstream effectors of this signaling pathway which may be critical for mediating the beneficial effects of AMPK on NASH and HCC.