Here, using HFFC diet-fed conditions lasting up to 52 weeks in duration or combining an HFFC diet with the liver fibrosis-inducing agent carbon tetrachloride and modulating the activity of Nrf1 and/or Nrf2 in differing disease stages, we investigate the hypothesis that Nrf1 and Nrf2 synergistically alleviate MASH and fibrosis and prevent HCC. Here, NRF1 is linked to hepatocellular carcinoma.