The Roles of Deubiquitination in Age-related Diseases

doi:10.12114/j.issn.1007-9572.2024.0357

Abstract

Abstract:

Deubiquitination, mediated by deubiquitinating enzymes (DUBs), represents a crucial class of post-translational protein modifications. Its primary mechanism involves in the interaction of DUBs with ubiquitinated target proteins, whereby the DUBs cleave or remove ubiquitin chains from these targets, subsequently restoring their expression levels and functional activities. This article systematically reviews the latest research progress on deubiquitination in age-related diseases, covering the types of DUBs, their roles in cellular aging, and the regulatory mechanisms in age-related diseases through different pathways. It also summarizes the research progress in the development of small-molecule drugs targeting DUBs and related mechanisms. This review demonstrates that as the body ages, factors such as decreased protein renewal function and oxidative damage lead to the accumulation of ubiquitinated proteins, resulting in cellular dysfunction. DUBs play an important and complex regulatory role in age-related diseases by modulating mechanisms such as protein homeostasis, mitochondrial function, and cell cycle in aging cells.

Key words: Aging, Age-related diseases, Deubiquitination, Deubiquitinating enzymes, Protein quality control, Mitochondrial function

摘要：

去泛素化修饰是由去泛素化酶（DUBs）介导的一类重要的蛋白质翻译后修饰，其主要机制是DUBs与泛素化靶蛋白相互作用，切割或去除靶蛋白的泛素链，进而恢复蛋白的表达水平和功能活性。本文系统性地综述了去泛素化修饰在衰老相关疾病中的最新研究进展，涵盖了DUBs的种类、DUBs在细胞衰老中的作用，以及不同机制对衰老相关疾病的调控，并总结了针对DUBs小分子药物开发以及相关机制的研究进展。本文表明，随着机体的衰老，蛋白更新功能减慢、氧化损伤等因素导致泛素化蛋白累积等，进而细胞出现功能障碍。DUBs通过调节衰老细胞的蛋白质稳态、线粒体功能、细胞周期等机制，在衰老相关疾病中发挥重要且复杂的调控作用。

XU Linhui,LI Pengfei,WU Miaomiao, et al. The Roles of Deubiquitination in Age-related Diseases[J]. Chinese General Practice, 2025, 28(09): 1143-1155. DOI: 10.12114/j.issn.1007-9572.2024.0357.
徐林慧,李鹏飞,吴苗苗等. 去泛素化修饰在衰老相关疾病中的研究进展[J]. 中国全科医学, 2025, 28(09): 1143-1155. DOI: 10.12114/j.issn.1007-9572.2024.0357.

Figures/Tables 3

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化合物名称（抑制剂）	靶向DUB	目前临床阶段	相关分子机制	参考文献
YCH2823	USP7	临床前期	p53-p21信号通路	[138]
P22077	USP7	临床前期	DNA损伤反应、NF-κB信号通路	[139]
Compound 41	USP7	临床前期	p53-p21信号通路	[140]
LDN-57444	UCH-L1	临床前期	调节氧化应激和线粒体功能	[141]
Compound-1/2	UCH-L1	临床前期	抗纤维化	[128]
6RK73、8RK64	UCH-L1	临床前期	细胞穿透探针与UCHL1活性位点结合	[142]
b-AP15	USP14、UCH-L5	临床前期	蛋白酶体活性、线粒体功能等	[143，144，145]
VLX1570	USP14、UCH-L5	临床前期（1/2阶段终止）	调节蛋白酶体活性	[146，147]
IU1	USP14	临床前期	与USP14催化结构域结合抑制其活性	[148]
WP1130	USP9x	临床前期	p53-p21信号通路	[149]
ST-539、FT385、MF094	USP30	临床前期	诱导线粒体自噬	[150，151，152]
MTX652	USP30	临床试验	诱导线粒体自噬	[153]
Spautin-1及其类似物	USP13	临床前期	增加蛋白酶体活性	[154]
compound 61	OTUB1、USP8	临床前期	抗增殖	[155]
PR-619	广谱抑制剂	临床前期	p53-p21信号通路、蛋白质稳态	[156]
gTE（激动剂）	A20	临床前期	抑制NF-kB通路	[157]
Farrerol（激动剂）	UCH-L3	临床前期	促进DNA修复和重编程	[158]

化合物名称（抑制剂）	靶向DUB	目前临床阶段	相关分子机制	参考文献
YCH2823	USP7	临床前期	p53-p21信号通路	[138]
P22077	USP7	临床前期	DNA损伤反应、NF-κB信号通路	[139]
Compound 41	USP7	临床前期	p53-p21信号通路	[140]
LDN-57444	UCH-L1	临床前期	调节氧化应激和线粒体功能	[141]
Compound-1/2	UCH-L1	临床前期	抗纤维化	[128]
6RK73、8RK64	UCH-L1	临床前期	细胞穿透探针与UCHL1活性位点结合	[142]
b-AP15	USP14、UCH-L5	临床前期	蛋白酶体活性、线粒体功能等	[143，144，145]
VLX1570	USP14、UCH-L5	临床前期（1/2阶段终止）	调节蛋白酶体活性	[146，147]
IU1	USP14	临床前期	与USP14催化结构域结合抑制其活性	[148]
WP1130	USP9x	临床前期	p53-p21信号通路	[149]
ST-539、FT385、MF094	USP30	临床前期	诱导线粒体自噬	[150，151，152]
MTX652	USP30	临床试验	诱导线粒体自噬	[153]
Spautin-1及其类似物	USP13	临床前期	增加蛋白酶体活性	[154]
compound 61	OTUB1、USP8	临床前期	抗增殖	[155]
PR-619	广谱抑制剂	临床前期	p53-p21信号通路、蛋白质稳态	[156]
gTE（激动剂）	A20	临床前期	抑制NF-kB通路	[157]
Farrerol（激动剂）	UCH-L3	临床前期	促进DNA修复和重编程	[158]