In the current study, the benefits and potential mechanisms of GPER1 in NASH progression were investigated, and we certified that the hepatic steatosis, inflammation, fibrosis, or insulin resistance in mouse NAFLD/NASH models were exacerbated by hepatocyte-specific GPER1 knockout but obviously mitigated by hepatic GPER1 activation. Here, GPER1 is linked to metabolic dysfunction-associated steatohepatitis.