We found that the hepatic loss of PON2 activity aggravated steatosis and oxidative stress under lipotoxic conditions, and our transcriptome analysis revealed that the loss of PON2 disrupts the activation of numerous functional pathways closely related to NAFLD pathogenesis, including mitochondrial respiratory capacity, lipid metabolism, and hepatic fibrosis and inflammation. The gene discussed is PON2; the disease is metabolic dysfunction-associated steatotic liver disease.