泛素蛋白酶体系统（UPS）是一种高度调控的蛋白质降解通路，对维持细胞内稳态至关重要。该系统在多个细胞过程中起着关键作用，包括DNA损伤修复、细胞周期检查点控制和免疫应答调控。近年来，由于其参与肿瘤发生和肿瘤进展，UPS作为癌症治疗的有希望的靶点而出现。本文旨在总结UPS的关键方面及其在癌症治疗中的意义。我们首先揭示UPS的基本组成部分，强调泛素、E1-E3连接酶和蛋白酶体在蛋白质降解中的作用。此外，我们讨论泛素化和蛋白酶体降解的复杂过程，强调通过各种信号通路实现的特异性和选择性。UPS的失调已与癌症的发展和进展相关。关键调控蛋白的异常泛素介导降解，如肿瘤抑制因子和致癌蛋白，可导致细胞无法受控地增殖、逃避凋亡和转移。我们概述了UPS在调节关键致癌途径中的关键作用，包括调控细胞周期蛋白、转录因子、复制应激成分和DNA损伤应答。UPS作为癌症治疗的靶点的不断认识，推动了小分子、肽和蛋白酶体抑制剂的发展，具有恢复细胞平衡和干扰肿瘤生长的潜力。我们概述了目前利用UPS开展的治疗策略，包括使用蛋白酶体抑制剂、去泛素化酶抑制剂和新型E3连接酶调节剂。我们进一步讨论了针对蛋白酶体抑制剂开发下一代药物的新兴策略。利用UPS进行癌症治疗为开发创新和有效的治疗策略提供了有希望的途径，为在与癌症的斗争中改善患者预后提供了希望。版权所有 © 2023 Elsevier B.V. 保留所有权利。

The ubiquitin proteasomal system (UPS) represents a highly regulated protein degradation pathway essential for maintaining cellular homeostasis. This system plays a critical role in several cellular processes, which include DNA damage repair, cell cycle checkpoint control, and immune response regulation. Recently, the UPS has emerged as a promising target for cancer therapeutics due to its involvement in oncogenesis and tumor progression. Here we aim to summarize the key aspects of the UPS and its significance in cancer therapeutics. We begin by elucidating the fundamental components of the UPS, highlighting the role of ubiquitin, E1-E3 ligases, and the proteasome in protein degradation. Furthermore, we discuss the intricate process of ubiquitination and proteasomal degradation, emphasizing the specificity and selectivity achieved through various signaling pathways. The dysregulation of the UPS has been implicated in cancer development and progression. Aberrant ubiquitin-mediated degradation of key regulatory proteins, such as tumor suppressors and oncoproteins, can lead to uncontrolled cell proliferation, evasion of apoptosis, and metastasis. We outline the pivotal role of the UPS in modulating crucial oncogenic pathways, including the regulation of cyclins, transcription factors, Replication stress components and DNA damage response. The increasing recognition of the UPS as a target for cancer therapeutics has spurred the development of small molecules, peptides, and proteasome inhibitors with the potential to restore cellular balance and disrupt tumor growth. We provide an overview of current therapeutic strategies aimed at exploiting the UPS, including the use of proteasome inhibitors, deubiquitinating enzyme inhibitors, and novel E3 ligase modulators. We further discuss novel emerging strategies for the development of next-generation drugs that target proteasome inhibitors. Exploiting the UPS for cancer therapeutics offers promising avenues for developing innovative and effective treatment strategies, providing hope for improved patient outcomes in the fight against cancer.Copyright © 2023 Elsevier B.V. All rights reserved.