上海交通大学陆炎等研究人员合作发现，通过抑制去泛素化酶RPN11可改善非酒精性脂肪肝的病情。相关论文于2024年8月14日在线发表在《细胞—代谢》杂志上。

研究人员探讨了去泛素化酶RPN11在非酒精性脂肪肝（NAFLD）和非酒精性脂肪性肝炎（NASH）中的作用。肝细胞特异性RPN11基因敲除小鼠对饮食诱导的肝脏脂肪变性、胰岛素抵抗和脂肪性肝炎具有保护作用。

从机理上讲，RPN11可去泛素化并稳定METTL3，从而增强酰基辅酶A（CoA）合成酶短链家族成员3（ACSS3）的m⁶A修饰和表达，ACSS3可生成丙酰基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-组蛋白丙酰化途径被激活。Capzimin对RPN11的药理抑制改善了小鼠的NAFLD、NASH和相关代谢紊乱，并降低了2D和3D培养的人类肝细胞中的脂质含量。这些结果表明，RPN11是NAFLD/NASH的新型调节因子，抑制RPN11具有治疗潜力。

据悉，NAFLD，包括其更严重的表现形式NASH，是一项全球性的公共卫生挑战。

附：英文原文

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

Author: Bing Zhou, Yunchen Luo, Hanqi Bi, Ni Zhang, Mingyue Ma, Zhixia Dong, Nana Ji, Shuo Zhang, Xiaoye Wang, Yuejun Liu, Xiaozhen Guo, Wei Wei, Cen Xie, Ling Wu, Xinjian Wan, Ming-Hua Zheng, Bing Zhao, Yao Li, Cheng Hu, Yan Lu

Issue&Volume: 2024-08-14

Abstract: Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestationnonalcoholic steatohepatitis (NASH), is a global public health challenge. Here, weexplore the role of deubiquitinating enzyme RPN11 in NAFLD and NASH. Hepatocyte-specificRPN11 knockout mice are protected from diet-induced liver steatosis, insulin resistance,and steatohepatitis. Mechanistically, RPN11 deubiquitinates and stabilizes METTL3to enhance the m6A modification and expression of acyl-coenzyme A (CoA) synthetaseshort-chain family member 3 (ACSS3), which generates propionyl-CoA to upregulate lipidmetabolism genes via histone propionylation. The RPN11-METTL3-ACSS3-histone propionylationpathway is activated in the livers of patients with NAFLD. Pharmacological inhibitionof RPN11 by Capzimin ameliorated NAFLD, NASH, and related metabolic disorders in miceand reduced lipid contents in human hepatocytes cultured in 2D and 3D. These resultsdemonstrate that RPN11 is a novel regulator of NAFLD/NASH and that suppressing RPN11has therapeutic potential for the treatment.

DOI: 10.1016/j.cmet.2024.07.014

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00285-7