肺癌是全球癌症相关死亡的首要原因,其发病机制复杂,临床治疗面临严峻挑战。近年来, 去泛素化酶在肿瘤发生发展中的调控作用备受关注。泛素特异性蛋白酶(ubiquitin-specific proteases, USPs)作为最大的去泛素化酶亚家族,通过精准调控关键信号通路蛋白的稳定性,在肺癌发生发展的多个环节发挥重要作用。本综述系统总结了USPs家族在调控肺癌细胞周期、细胞增殖、凋亡逃逸、侵袭转移、免疫微环境重塑及治疗耐药中的分子机制,重点探讨了USP7、USP9X 和USP22等关键成员通过p53、程序性死亡配体1(programmed death-1,PD-L1)和Wnt/β-连环蛋白等信号通路调控肺癌进程的分子网络,全面分析了靶向USPs的小分子抑制剂研发最新进展并探讨了其在肺癌精准治疗中的应用前景,以期为开发新型诊疗策略提供理论依据。

Lung cancer is the leading cause of cancer-related deaths worldwide,with a complex pathogenesis and significant challenges in clinical treatment.In recent years, the regulatory role of deubiquitinating enzymes in tumorigenesis and progression has garnered increasing attention. As the largest subfamily of deubiquitinating enzymes, ubiquitin-specific proteases (USPs) exert multidimensional regulatory effects on the initiation and progression of lung cancer by precisely modulating the stability of key signaling pathway proteins.This review systematically summarizes the molecular mechanisms by which the USPs family regulates the lung cancer cell cycle progression, proliferation,apoptosis evasion,invasion and metastasis, immune microenvironment remodeling, and therapy resistance. It highlights the molecular networks of key members, such as USP7, USP9X, and USP22, in modulating lung cancer progression through critical signaling pathways, including p53, programmed death ligand 1 (PD-L1), and Wnt/β-catenin. Additionally, the review comprehensively analyzes the latest advances in the development of small-molecule inhibitors targeting USPs and explores their potential applications in precision therapy for lung cancer, aiming to provide a theoretical foundation for novel diagnostic and therapeutic strategies.