Hepatocyte-specific overexpression of SQLE triggers spontaneous insulin resistance and NAFLD and induces the activation of SREBP1c, acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl coenzyme A (SCA) through the promotion of cholesterol synthesis and accumulation, and the binding of carbonic anhydrase 3 (CA3) and stearoyl-CoA desaturase1 (SCD1) leads to the expression of lipogenesis and triglyceride biosynthesis genes, thereby inducing de novo hepatic lipogenesis and the activation of the NF-κB inflammatory pathway, which drives the pathogenesis and progression of NASH. Here, SREBF1 is linked to metabolic dysfunction-associated steatohepatitis.