泛素特异性蛋白酶7在炎症性疾病中的研究进展
Research Progress of Ubiquitin-Specific Protease 7 in Inflammatory Diseases
DOI: 10.12677/pi.2026.153024, PDF,   
作者: 陈 雪, 戴 岳*：中国药科大学中药学院，江苏 南京
关键词: 去泛素化酶；USP7；炎症性疾病；靶向治疗；Deubiquitinating Enzyme； USP7； Inflammatory Disease； Targeted Therapy
摘要: 泛素特异性蛋白酶7 (USP7)通过调控关键蛋白的稳定性，在细胞生命活动中扮演着重要角色。近年来的研究表明，USP7在炎症信号网络中亦发挥核心调节作用。本文系统综述USP7在多种炎症性疾病(炎症性肠病、脓毒症/急性肺损伤、心血管炎症、骨关节炎、急性胰腺炎、过敏性炎症等)中的作用与研究进展。尽管USP7小分子抑制剂在动物模型中显示出良好的抗炎效果，但其底物谱的细胞特异性、抑制剂的选择性与安全性等问题仍是制约临床转化的主要因素。未来需进一步阐明USP7在炎症微环境中的调控机制，以推动其成为有效的抗炎治疗靶点。
Abstract: Ubiquitin-specific protease 7 (USP7) plays an essential role in cellular homeostasis by regulating the stability of numerous key proteins. Recent studies have increasingly recognized that USP7 also serves as a central modulator within inflammatory signaling networks. This review summarizes the current research progress regarding the functional roles of USP7 in a spectrum of inflammatory diseases, including inflammatory bowel disease, sepsis/acute lung injury, cardiovascular inflammation, osteoarthritis, acute pancreatitis, and allergic inflammation. Although small-molecule inhibitors targeting USP7 have demonstrated promising anti-inflammatory efficacy in animal models, the cell-type-specific substrate profile of USP7, together with concerns regarding the selectivity and long-term safety of current inhibitors, remains a major barrier to clinical translation. Further elucidation of the regulatory mechanisms of USP7 within the inflammatory microenvironment is therefore required to advance its development as an effective anti-inflammatory therapeutic target.
文章引用：陈雪, 戴岳. 泛素特异性蛋白酶7在炎症性疾病中的研究进展[J]. 药物资讯, 2026, 15(3): 215-222. https://doi.org/10.12677/pi.2026.153024

参考文献

[1] Wang, L., Zhang, Y., Yu, T. and Wu, H. (2024) The Role and Mechanism of Deubiquitinase USP7 in Tumor-Associated Inflammation. Biomedicines, 12, Article 2734. [Google Scholar] [CrossRef] [PubMed]
[2] El-Hamaky, A.A., El-Hamamsy, M.H., El-Moselhy, T.F., Sharafeldin, N. and Tawfik, H.O. (2025) Therapeutic Targeting of Ubiquitin-Specific Protease 7 (USP7): Mechanistic Insights, Dysregulation, and Advances in Drug Discovery. European Journal of Medicinal Chemistry, 296, Article 117872. [Google Scholar] [CrossRef] [PubMed]
[3] Rougé, L., Bainbridge, T.W., Kwok, M., Tong, R., Di Lello, P., Wertz, I.E., et al. (2016) Molecular Understanding of USP7 Substrate Recognition and C-Terminal Activation. Structure, 24, 1335-1345. [Google Scholar] [CrossRef] [PubMed]
[4] Guo, N., Wang, B., Zhang, Y., Kang, H., Nie, H., Feng, M., et al. (2024) USP7 as an Emerging Therapeutic Target: A Key Regulator of Protein Homeostasis. International Journal of Biological Macromolecules, 263, Article 130309. [Google Scholar] [CrossRef] [PubMed]
[5] Gros, B. and Kaplan, G.G. (2023) Ulcerative Colitis in Adults: A review. JAMA, 330, 951-965. [Google Scholar] [CrossRef] [PubMed]
[6] Xu, W., Hua, Z., Wang, Y., Tang, W., Ge, W., Chen, Y., et al. (2025) Redox‐Induced Stabilization of AMBRA1 by USP7 Promotes Intestinal Oxidative Stress and Colitis through Antagonizing DUB3‐Mediated NRF2 Deubiquitination. Advanced Science, 12, e2411320. [Google Scholar] [CrossRef] [PubMed]
[7] Zhao, Y., Huang, L., Qin, W., Zhang, B., Yang, Y., Chen, X., et al. (2026) Dual Covalent Targeting of STING Cysteines 292/309 Disrupts Functional Oligomerization and Enables Potent Antagonist Development. Advanced Science, 24, e22764. [Google Scholar] [CrossRef] 
[8] Zhu, Y., Guo, Y., Guo, P., Zhang, J., He, Y., Xia, Y., et al. (2025) Estrogen Receptor β Activation Alleviates Inflammatory Bowel Disease by Suppressing NLRP3-Dependent Il-1β Production in Macrophages via Downregulation of Intracellular Calcium Level. Journal of Advanced Research, 71, 571-584. [Google Scholar] [CrossRef] [PubMed]
[9] Palazón‐Riquelme, P., Worboys, J.D., Green, J., Valera, A., Martín‐Sánchez, F., Pellegrini, C., et al. (2018) USP7 and USP47 Deubiquitinases Regulate NLRP3 Inflammasome Activation. EMBO reports, 19, e44766. [Google Scholar] [CrossRef] [PubMed]
[10] van Loosdregt, J., Fleskens, V., Fu, J., Brenkman, A.B., Bekker, C.P.J., Pals, C.E.G.M., et al. (2013) Stabilization of the Transcription Factor Foxp3 by the Deubiquitinase USP7 Increases Treg-Cell-Suppressive Capacity. Immunity, 39, 259-271. [Google Scholar] [CrossRef] [PubMed]
[11] Lu, Y., Kim, N., Jiang, Y., Zhang, H., Zheng, D., Zhu, F., et al. (2018) Cambogin Suppresses Dextran Sulphate Sodium‐induced Colitis by Enhancing Treg Cell Stability and Function. British Journal of Pharmacology, 175, 1085-1099. [Google Scholar] [CrossRef] [PubMed]
[12] Xu, H., Wang, Q., Fan, J., et al. (2025) Deubiquitinase USP7 Regulates Neutrophil Extracellular Trap Formation and Inflammation in Lipopolysaccharide-Treated Mice through ICAM-1 Expression. Kaohsiung Journal of Medical Sciences, e70133.
[13] Liu, Z., Shi, X., Ke, T., Yan, Z., Xiong, L. and Tang, F. (2025) USP7 Promotes Endothelial Activation to Aggravate Sepsis-Induced Acute Lung Injury through Pdk1/Akt/NF-κB Signaling Pathway. Cell Death Discovery, 11, Article No. 183. [Google Scholar] [CrossRef] [PubMed]
[14] Zhao, X., Ji, F., Li, H., Zhu, H., Zhao, Z., Ling, J., et al. (2020) P22077 Inhibits LPS-Induced Inflammatory Response by Promoting K48-Linked Ubiquitination and Degradation of Traf6. Aging, 12, 10969-10982. [Google Scholar] [CrossRef] [PubMed]
[15] Xiang, Z., Lu, X. and Zhang, L. (2025) TGFBR2 Accelerates the Oxidative Stress and Inflammation in Septic Acute Lung Injury via Mettl14-Mediated M6a Modification or Usp7-Regulated Deubiquitination. Shock.
https://journals.lww.com/shockjournal/abstract/9900/tgfbr2_accelerates_the_oxidative_stress_and.768.aspx
[16] Colleran, A., Collins, P.E., O’Carroll, C., Ahmed, A., Mao, X., McManus, B., et al. (2013) Deubiquitination of Nf-Κb by Ubiquitin-Specific Protease-7 Promotes Transcription. Proceedings of the National Academy of Sciences, 110, 618-623. [Google Scholar] [CrossRef] [PubMed]
[17] Qian, G., Wang, Y., Yao, H., Zhang, Z., Wang, W., Xu, L., et al. (2025) Involvement of USP7 in Aggravating Kawasaki Disease by Promoting TGFβ2 Signaling Mediated Endothelial-Mesenchymal Transition and Coronary Artery Remodeling. International Immunopharmacology, 146, Article 113823. [Google Scholar] [CrossRef] [PubMed]
[18] Gong, X., Li, Y., He, Y. and Zhou, F. (2022) USP7-SOX9-miR-96-5p-NLRP3 Network Regulates Myocardial Injury and Cardiomyocyte Pyroptosis in Sepsis. Human Gene Therapy, 33, 1073-1090.
[19] Gu, Y., Ren, K., Wang, Y., Wang, S., Yu, X., Xu, L., et al. (2022) Administration of USP7 Inhibitor P22077 Inhibited Cardiac Hypertrophy and Remodeling in Ang II-Induced Hypertensive Mice. Frontiers in Pharmacology, 13, Article ID: 1021361. [Google Scholar] [CrossRef] [PubMed]
[20] Xue, Q., Yang, D., Zhang, J., Gan, P., Lin, C., Lu, Y., et al. (2020) USP7, Negatively Regulated by miR‐409‐5p, Aggravates Hypoxia‐Induced Cardiomyocyte Injury. APMIS, 129, 152-162. [Google Scholar] [CrossRef] [PubMed]
[21] Zhang, Y. and Zhang, Y. (2024) Knockdown of USP7 Alleviates Atherosclerosis in ApoE-Deficient Mice by Regulating EZH2 Expression. Open Life Sciences, 19, Article 20220929. [Google Scholar] [CrossRef] [PubMed]
[22] Yuan, Z., Chen, G., Li, Y., Zhao, Z. and Zhang, H. (2025) Deubiquitinating Enzymes in Osteoarthritis: From Mechanisms to Therapeutic. Orthopedic Reviews, 17, Article No. 144733. [Google Scholar] [CrossRef] 
[23] Liu, G., Liu, Q., Yan, B., Zhu, Z. and Xu, Y. (2021) USP7 Inhibition Alleviates H2O2-Induced Injury in Chondrocytes via Inhibiting NOX4/NLRP3 Pathway. Frontiers in Pharmacology, 11, Article ID: 617270. [Google Scholar] [CrossRef] [PubMed]
[24] Zhou, F., Wang, Z., Li, H., Wang, D., Wu, Z., Bai, F., et al. (2025) USP7 Inhibition Promotes Early Osseointegration in Senile Osteoporotic Mice. Journal of Dental Research, 104, 86-96. [Google Scholar] [CrossRef] [PubMed]
[25] Trikudanathan, G., Yazici, C., Evans Phillips, A. and Forsmark, C.E. (2024) Diagnosis and Management of Acute Pancreatitis. Gastroenterology, 167, 673-688. [Google Scholar] [CrossRef] [PubMed]
[26] Peng, F. and Deng, X. (2025) Ubiquitin-Specific Protease 7 Exacerbates Acute Pancreatitis Progression by Enhancing ATF4-Mediated Autophagy. In Vitro Cellular & Developmental Biology-Animal, 61, 320-330. [Google Scholar] [CrossRef] [PubMed]
[27] Wu, Y., Yao, X., Yu, Q., Yan, Q., Huang, X., Ke, H., et al. (2025) Ubiquitin-Specific Protease 7 Regulates Macrophage Polarization via Pyruvate Kinase M2-Mediated Metabolic Reprogramming in Severe Acute Pancreatitis. Cell Death & Disease, 16, Article No. 764. [Google Scholar] [CrossRef] 
[28] Kumagai, J., Kiuchi, M., Kokubo, K., Yagyu, H., Nemoto, M., Tsuji, K., et al. (2023) The USP7-STAT3-Granzyme-Par-1 Axis Regulates Allergic Inflammation by Promoting Differentiation of Il-5-Producing Th2 Cells. Proceedings of the National Academy of Sciences, 120, e2302903120. [Google Scholar] [CrossRef] [PubMed]
[29] Liu, J., Liu, Z., Geng, X., Wu, Y., Mo, L., Liao, Y., et al. (2026) KDM5A: A Master Epigenetic Regulator of Th2 Immunity and Allergic Disease Pathogenesis. Immunology, 177, 467-480. [Google Scholar] [CrossRef] 
[30] Wang, Y., Mu, H., Yang, B., Yang, C., Dong, W. and Wang, J. (2025) USP7-A Novel Target for Controlling Periodontal Inflammation through Modulation of Macrophage Polarization. Immunology Letters, 273, Article 106981. [Google Scholar] [CrossRef] [PubMed]
[31] Zhu, Y., Zong, M., Hu, L., Wan, J., Zong, L. and Xu, J. (2025) USP7 Deficiency Promotes Diabetic Wound Healing by Repressing Gata3-Mediated Pro-Inflammatory Macrophage Polarization. Molecular and Cellular Endocrinology, 599, Article 112489. [Google Scholar] [CrossRef] [PubMed]
[32] Aihemaiti, S., Wei, K., Abulimiti, D., Kan, Y., Zhang, Z., Tao, S., et al. (2026) USP7 Inhibition Promotes Wound Healing by Suppressing M1 Macrophage Polarization via NF-κB/MAPK Signaling Pathway. International Immunopharmacology, 168, Article 115791. [Google Scholar] [CrossRef] 
[33] Yan, Q., Fang, Q., Chen, Z., Chen, L. and Du, J. (2025) RNF2 Modulates Lipid Metabolism and Inflammation in Alcohol-Associated Liver Disease by Interacting with USP7. International Journal of Biological Sciences, 21, 3306-3323. [Google Scholar] [CrossRef] [PubMed]
[34] Park, J., Lim, K. and Baek, K. (2015) Annexin-1 Regulated by HAUSP Is Essential for UV-Induced Damage Response. Cell Death & Disease, 6, e1654-e1654. [Google Scholar] [CrossRef] [PubMed]
[35] Chen, C., Song, J., Wang, J., Xu, C., Chen, C., Gu, W., et al. (2017) Synthesis and Biological Evaluation of Thiazole Derivatives as Novel USP7 Inhibitors. Bioorganic & Medicinal Chemistry Letters, 27, 845-849. [Google Scholar] [CrossRef] [PubMed]
[36] O’Dowd, C.R., Helm, M.D., Rountree, J.S.S., Flasz, J.T., Arkoudis, E., Miel, H., et al. (2018) Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors. ACS Medicinal Chemistry Letters, 9, 238-243. [Google Scholar] [CrossRef] [PubMed]
[37] Gavory, G., O’Dowd, C.R., Helm, M.D., Flasz, J., Arkoudis, E., Dossang, A., et al. (2018) Discovery and Characterization of Highly Potent and Selective Allosteric USP7 Inhibitors. Nature Chemical Biology, 14, 118-125. [Google Scholar] [CrossRef] [PubMed]
[38] Song, Y., Ren, X., Xiong, J., Wang, W., Zhao, Q., Chang, J., et al. (2025) Ubiquitin-Specific Protease 7 (USP7) as a Promising Therapeutic Target for Drug Discovery: From Mechanisms to Therapies. Journal of Medicinal Chemistry, 68, 7914-7931. [Google Scholar] [CrossRef] [PubMed]
[39] Khamjan, N.A. (2025) Targeting Deubiquitinating Enzymes in Cancer: Navigating Context-Dependence for Precision Medicine. Oncologie, 28, 33-57. [Google Scholar] [CrossRef] 
[40] Mitxitorena, I., Somma, D., Mitchell, J.P., Lepistö, M., Tyrchan, C., Smith, E.L., et al. (2020) The Deubiquitinase USP7 Uses a Distinct Ubiquitin-Like Domain to Deubiquitinate NF-ĸB Subunits. Journal of Biological Chemistry, 295, 11754-11763. [Google Scholar] [CrossRef] [PubMed]
[41] Shi, J., Wang, L., Zeng, X., Xie, C., Meng, Z., Campbell, A., et al. (2024) Precision-Engineered PROTACs Minimize Off-Tissue Effects in Cancer Therapy. Frontiers in Molecular Biosciences, 11, Article ID: 1505255. [Google Scholar] [CrossRef] [PubMed]
[42] Bhole, R.P., Labhade, S. and Gurav, S.S. (2025) Conquering PROTAC Molecular Design and Drugability. Bioanalysis, 17, 455-470. [Google Scholar] [CrossRef] [PubMed]
[43] Zhou, G., Tan, J., Zhang, P., Zhou, Z., Zhang, L. and Zhang, Z. (2025) Mechanistic Insights and Therapeutic Potentials of Ubiquitin‐Proteasome System in Non‐Small Cell Lung Cancer. Cell Proliferation, 58, e70050. [Google Scholar] [CrossRef] [PubMed]
[44] 于万晴, 陈超, 杨亚玺, 等. 靶向泛素特异性蛋白酶7的药物研究进展[J]. 药学学报, 2025, 60(8): 2453-2465.