Sirtuin 2 (SIRT2) deficiency promoted lipid deposition and inflammation in cells accompanied with HFCS (high-fat/high-cholesterol/high-sucrose)-induced obesity, hepatic steatosis, and an aggravated metabolic profile, indicating SIRT2 deficiency advances NAFLD–NASH progression. This evidence concerns the gene SIRT2 and metabolic dysfunction-associated steatohepatitis.