Amelioration of nonalcoholic fatty liver disease by inhibiting the deubiquitylating enzyme RPN11

Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation nonalcoholic steatohepatitis (NASH), is a global public health challenge. Here, we explore the role of deubiquitinating enzyme RPN11 in NAFLD and NASH. Hepatocyte-specific RPN11 knockout mice are protected from diet-induced liver steatosis, insulin resistance, and steatohepatitis. Mechanistically, RPN11 deubiquitinates and stabilizes METTL3 to enhance the m6A modification and expression of acyl-coenzyme A (CoA) synthetase short-chain family member 3 (ACSS3), which generates propionyl-CoA to upregulate lipid metabolism genes via histone propionylation. The RPN11-METTL3-ACSS3-histone propionylation pathway is activated in the livers of patients with NAFLD. Pharmacological inhibition of RPN11 by Capzimin ameliorated NAFLD, NASH, and related metabolic disorders in mice and reduced lipid contents in human hepatocytes cultured in 2D and 3D. These results demonstrate that RPN11 is a novel regulator of NAFLD/NASH and that suppressing RPN11 has therapeutic potential for the treatment. [Display omitted] •Hepatocyte-specific RPN11 knockout mice are protected from liver steatosis•RPN11 deubiquitinates and stabilizes METTL3 to enhance the m6A modification of ACSS3•RPN11-METTL3-ACSS3 axis upregulates lipid-related genes via histone propionylation•RPN11 inhibitor could alleviate NAFLD and NASH in mice Nonalcoholic fatty liver disease has become a significant global health challenge. In this study, Zhou et al. reveal that RPN11, a deubiquitinating enzyme, plays an important role in NAFLD and NASH. These insights suggest that suppressing RPN11 may offer a new therapeutic strategy for treating metabolic liver diseases.