High fat, fructose, and cholesterol (HFFC) diet-fed mice with a coinciding 1 to 3 weeks of hepatocyte deficiency for Nrf1 and Nrf2, but not either alone, exhibited severe MASH due to increased hepatic lipid storage, altered bile acid metabolism, and oxidative damage, whereas Nrf1 deficiency alone was sufficient to increase hepatic inflammation. This evidence concerns the gene NRF1 and metabolic dysfunction-associated steatohepatitis.