SENP1 is markedly downregulated in the livers of individuals with NAFLD or NASH and that SENP1 absence from mouse hepatocytes hastens the development of spontaneous NASH-related phenotypes, including liver inflammation, lipid accumulation, liver damage, and fibrosis, in a RIPK1 kinase-dependent manner. Here, SENP1 is linked to metabolic dysfunction-associated steatohepatitis.