Using multiple mouse models with NASH induced by long-term HFHC or HFMCD feeding, we found that hepatocyte-specific DUSP22 ablation (DUSP22HepKO) using CRISPR/Cas9 system prominently exacerbated hepatic steatosis, inflammation, and fibrosis; however, AAV8-mediated DUSP22 overexpression (DUSP22HepOE) considerably conferred protection against NASH progression after HFHC or HFMCD challenge, which was confirmed by lentivirus-mediated DUSP22 (LV-DUSP22) ex vivo gene therapy. This evidence concerns the gene DUSP22 and fatty liver disease.