文献类型：期刊文献

英文题名：Spotlights on ubiquitin-specific proteases in lung cancer: from multifaceted pathophysiological mechanisms to potential therapeutic targets

作者：Shen, Xiaoyun[1];Wang, Ruoqi[1];Su, Fei[2];Guo, Juanjuan[1];Zhao, Da[2];Yuan, Fangyun[2];Zhang, Tao[2];Hou, Xiaoming[1,2]

第一作者：Shen, Xiaoyun

通信作者：Hou, XM[1];Zhang, T[2];Hou, XM[2]

机构：[1]Gansu Univ Chinese Med, Sch Clin Med 1, Lanzhou, Gansu, Peoples R China;[2]Lanzhou Univ, Hosp 1, Dept Oncol, Lanzhou, Gansu, Peoples R China

第一机构：甘肃中医药大学

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Sch Clin Med 1, Lanzhou, Gansu, Peoples R China;[2]corresponding author), Lanzhou Univ, Hosp 1, Dept Oncol, Lanzhou, Gansu, Peoples R China.|[10735]甘肃中医药大学;

年份：2026

卷号：14

外文期刊名：PEERJ

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001682323300001)】；

基金：This work was supported by grants from the National Natural Science Foundation of China (NO. 82460535 and 82260518), the Key R&D Program of Gansu Province (22YF7FA086 and 25YFFA049), the Joint Research Foundation of Gansu Province(25JRRA1245 and 23JRRA1497), the Key Talent Project of the Organization Department of the Gansu Provincial Committee of the Communist Party of China (2025RCXM036), the Gansu Provincial Clinical Research Center for Thoracic Oncology: (21JR7RA390), and the General Program of Gansu Provincial Natural Science Foundation (23JRRA0928 and 23JRRA1607, Lanzhou City Science and Technology Program: 2020-ZD-74; Cheng guan District Science and Technology Program: 2021RCCX0008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

语种：英文

外文关键词：Ubiquitin-specific proteases; Lung cancer; And deubiquitination

摘要：Lung cancer ranks as the leading cause of cancer-related mortality worldwide, characterised by complex molecular mechanisms and high therapeutic resistance. Ubiquitin-specific proteases, as core members of the deubiquitinating enzyme family, extensively participate in the initiation, progression, metastasis, and treatment resistance of lung cancer by regulating the stability of key proteins. Recent studies indicate that multiple Ubiquitin-Specific Proteases (USP) family members play pivotal roles in lung cancer: Ubiquitin-Specific Peptidase 7 (USP7) promotes proliferation and osimertinib resistance in non-small cell lung cancer by stabilising proteins such as ER beta, c-Abl, and KRAS; Ubiquitin-Specific Peptidase 9, X-linked (USP9X) mediates radiotherapy resistance by regulating KDM4C and REV1; USP10 influences cellular metabolism and chemotherapy sensitivity via PTEN/AKT/mTOR and HDAC6 pathways; Ubiquitin-Specific Peptidase 14 (USP14) enhances tumour migration by regulating beta-catenin and Acf7 stability; Ubiquitin-Specific Peptidase 22 (USP22) amplifies tumour stem cell properties and suppresses ferroptosis via EGFR and BMI1 signalling; Ubiquitin-Specific Peptidase 35 (USP35) and Ubiquitin-Specific Peptidase 38 (USP38) respectively modulate apoptosis resistance and proliferation through BIRC3 and KLF5; while Ubiquitin-Specific Peptidase 39 (USP39) influences mitochondrial metabolism via PDHA, thereby promoting tumour growth. This paper systematically reviews the mechanisms of action of the aforementioned USPs in multiple key signalling pathways, including KRAS, TGF-beta/SMAD, ferroptosis, and DNA damage repair. It further explores the potential value of small-molecule inhibitors targeting USPs (such as P5091, IU1, and gentiopicroside) in reversing drug resistance, inducing apoptosis, and enhancing immunotherapy. Nevertheless, current research remains subject to certain limitations, including insufficient systematic and synergistic understanding of USP family members' functions, poor inhibitor selectivity and preclinical toxicity concerns, as well as unresolved functional heterogeneity across different molecular subtypes of lung cancer. This paper reviews the molecular mechanisms and targeting strategies of USPs in lung cancer based on a systematic literature search of PubMed and Web of Science databases. It further explores their potential applications in precision lung cancer therapy, providing theoretical foundations and directional guidance for future research.