Our studies suggest that the deletion of Nrf2, a lipid-metabolism regulating gene, disrupts fatty acid composition and homeostasis, causing the evolution of the “benign” SS to develop into NASH, through regulating of the MUFA/TFA ratio up and the PUFA/TFA ratio down, in conjunction with the increased hepatic concentrations of C18: 1, C20: 1, C12: 0, C22: 0, and C18: 3 in the liver. Here, NFE2L2 is linked to metabolic dysfunction-associated steatohepatitis.