Herein, we found that administrated AgNPs significantly induced worsened hepatic steatosis and increased liver injury in mice due to the hyperactivation of SREBP-1c-mediated de novo lipogenesis (DNL), proinflammatory activation of cytokines, and elevated induction of oxidative stress and global DNA methylation, indicating the potential exacerbation of NAFLD and development NASH. This evidence concerns the gene SREBF1 and metabolic dysfunction-associated steatotic liver disease.