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 with no approved pharmacological therapies. Here, we reveal an indispensable role for the deubiquitinating enzyme RPN11 in the development of NAFLD and NASH. Ablation of hepatic RPN11 markedly protected mice from several diets-induced liver steatosis, insulin resistance and steatohepatitis, whereas RPN11 overexpression had the opposite effects. Mechanistically, RPN11 interacts with and stabilizes METTL3 via deubiquitination initiated at lysine 241, to increase the m6A modification and expression of acyl-CoA synthetase short chain family member 3 (Acss3). RPN11-Acss3 axis generates propionyl-CoA and functions in histone propionylation to transcriptionally upregulate lipid metabolism-related genes. Of pathophysiological significance, RPN11-METTL3-Acss3-histone propionylation modification pathway is activated in the livers of patients with NAFLD and positively correlated with hepatic triglyceride contents. More importantly, pharmacological inhibition of RPN11 by Capzimin showed dramatic beneficial effects in ameliorating NAFLD, NASH and related metabolic disorders in mice. Capzimin also reduces intracellular lipid contents in human primary hepatocytes cultured in 2D and 3D spheroids. Together, these results demonstrate that RPN11 is essential for the development of NAFLD/NASH and that suppressing RPN11 has therapeutic potential for the treatment.