Zhou B, Luo Y, Bi H, et al, Amelioration of nonalcoholic fatty liver disease by inhibiting the deubiquitylating enzyme RPN11, Cell Metab, 2024. (IF:27.287)

Abstract: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are global public health issues. Recent research has revealed that the deubiquitinating enzyme RPN11 plays a key role in the development of NAFLD and NASH. By specifically knocking out the RPN11 gene in hepatocytes of mice, researchers found that these mice were resistant to liver fat accumulation, insulin resistance, and hepatitis caused by a high-fat diet. The study further uncovered that RPN11 enhances the m6A modification and expression of ACSS3 by deubiquitinating and stabilizing METTL3, with ACSS3 producing propionyl-CoA to upregulate lipid metabolism genes through histone propionylation. In the livers of patients with NAFLD, the RPN11-METTL3-ACSS3-propionylation pathway is activated. The pharmacological inhibition of RPN11 with Capzimin can improve NAFLD, NASH, and related metabolic disorders in mice and reduce lipid content in 2D and 3D cultured human hepatocytes. RPN11 is a potential therapeutic target, and inhibiting RPN11 may become a new strategy for treating NAFLD/NASH.

摘要：非酒精性脂肪肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）是全球性的公共卫生问题。最新研究显示，去泛素化酶RPN11在NAFLD和NASH的发展中扮演关键角色。通过在小鼠中特异性敲除肝细胞的RPN11基因，研究人员发现这些小鼠能够抵抗由高脂饮食引起的肝脂肪积累、胰岛素抵抗和肝炎。研究进一步揭示了RPN11通过去泛素化和稳定METTL3，增强了ACSS3的m6A修饰和表达，ACSS3进一步产生丙酰-CoA，通过组蛋白丙酰化上调脂质代谢基因。在NAFLD患者的肝脏中，RPN11-METTL3-ACSS3-组蛋白丙酰化信号通路被激活。使用Capzimin这种药物抑制RPN11可以改善小鼠的NAFLD、NASH及相关代谢紊乱，并减少2D和3D培养的人类肝细胞中的脂质含量。RPN11是一个潜在的治疗靶点，抑制RPN11可能成为治疗NAFLD/NASH的新策略。