{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T08:48:36Z","timestamp":1782895716077,"version":"3.54.5"},"reference-count":108,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>OTU deubiquitinases are linkage-sensitive ubiquitin editors that regulate immune circuits, human immunopathology, and emerging therapeutic opportunities. By remodeling K48-, K63-, and linear ubiquitin chains, they control protein stability, scaffold assembly, and signal amplitude across nuclear factor \u03baB (NF-\u03baB), and tumor-immune pathways. Individual OTUs have been linked to inflammation, infection, autoimmunity, metabolic dysfunction, and cancer, yet disease-by-disease descriptions often obscure their shared mechanistic logic. We therefore organize current evidence around chain selectivity, substrate context, and immune-circuit function. We examine innate inflammatory regulation, adaptive and tumor immunity, and the emerging therapeutic landscape, including covalent inhibitors, engineered binders, repurposed compounds, and induced-proximity platforms. We also distinguish catalytic from non-catalytic functions, define determinants of context dependence, and propose practical criteria for translational target ranking. This framework positions OTU enzymes not only as an isolated catalogue of disease factors, but also as a mechanistically coherent field centered on mechanism-guided target ranking and disease-specific biological context.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1843621","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T08:26:00Z","timestamp":1782894360000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["OTU deubiquitinases as immune-circuit editors: from human immunopathology to therapeutic prioritization"],"prefix":"10.3389","volume":"17","author":[{"given":"Yi","family":"Guo","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology","place":["Xianning, China"]},{"name":"Hubei Key Laboratory of Environmental Risks and Related Diseases Precision Control, Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Song","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxin","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Xiong","sequence":"additional","affiliation":[{"name":"School of Health Management, Xianning Vocational Technical College","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Bao","sequence":"additional","affiliation":[{"name":"School of Public Health and Nursing, Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surui","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhan","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Stomatology and Ophthalmology, Xianning Medical College, Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xijun","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyuan","family":"Liao","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfen","family":"Bao","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Qu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology","place":["Xianning, China"]},{"name":"Hubei Key Laboratory of Environmental Risks and Related Diseases Precision Control, Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Oncology, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology","place":["Xianning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.22.010605.093503","article-title":"Modification of proteins by ubiquitin and ubiquitin-like proteins","volume":"22","author":"Kerscher","year":"2006","journal-title":"Annu Rev Cell Dev Biol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060310-170328","article-title":"The ubiquitin code","volume":"81","author":"Komander","year":"2012","journal-title":"Annu Rev Biochem"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2013.06.027","article-title":"Regulation of proteolysis by human deubiquitinating enzymes","volume":"1843","author":"Eletr","year":"2014","journal-title":"Biochim Biophys Acta"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.046","article-title":"OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis","volume":"154","author":"Mevissen","year":"2013","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s11684-019-0734-4","article-title":"The function and regulation of OTU deubiquitinases","volume":"14","author":"Du","year":"2020","journal-title":"Front Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41418-020-00675-x","article-title":"Ubiquitin-dependent and -independent functions of OTULIN in cell fate control and beyond","volume":"28","author":"Weinelt","year":"2021","journal-title":"Cell Death Differ"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.014","article-title":"OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin","volume":"153","author":"Keusekotten","year":"2013","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3218","article-title":"Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis","volume":"17","author":"Yuan","year":"2015","journal-title":"Nat Cell Biol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1016\/j.cell.2016.07.019","article-title":"The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity","volume":"166","author":"Damgaard","year":"2016","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.3c00227","article-title":"Cellular validation of a chemically improved inhibitor identifies monoubiquitination on OTUB2","volume":"18","author":"Gan","year":"2023","journal-title":"ACS Chem Biol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.molmed.2025.05.006","article-title":"OTU deubiquitinases in disease: roles and targeting","volume":"32","author":"Deng","year":"2026","journal-title":"Trends Mol Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70036","article-title":"Deubiquitinases as novel therapeutic targets for diseases","volume":"5","author":"Xian","year":"2024","journal-title":"MedComm (2020)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.32604\/or.2025.063644","article-title":"Deubiquitinating enzyme OTUDs: focus on cancers and antiviral response","volume":"33","author":"Chen","year":"2025","journal-title":"Oncol Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/s0968-0004(99)01530-3","article-title":"A novel superfamily of predicted cysteine proteases from eukaryotes, viruses and Chlamydia pneumoniae","volume":"25","author":"Makarova","year":"2000","journal-title":"Trends Biochem Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nature09297","article-title":"Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1","volume":"466","author":"Nakada","year":"2010","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3558","article-title":"Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing","volume":"17","author":"Chen","year":"2016","journal-title":"Nat Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900305","article-title":"OTUD1 negatively regulates type I IFN induction by disrupting noncanonical ubiquitination of IRF3","volume":"204","author":"Zhang","year":"2020","journal-title":"J Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110920","article-title":"Opposing effects of deubiquitinase OTUD3 in innate immunity against RNA and DNA viruses","volume":"39","author":"Cai","year":"2022","journal-title":"Cell Rep"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00531-5","article-title":"OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING","volume":"18","author":"Guo","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.coi.2020.10.013","article-title":"The innate immune system and cell death in autoinflammatory and autoimmune disease","volume":"67","author":"Place","year":"2020","journal-title":"Curr Opin Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1863","article-title":"The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors","volume":"11","author":"Kawai","year":"2010","journal-title":"Nat Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"a036418","DOI":"10.1101\/cshperspect.a036418","article-title":"A20 at the crossroads of cell death, inflammation, and autoimmunity","volume":"12","author":"Martens","year":"2020","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/j.immuni.2013.03.008","article-title":"Dimerization and ubiquitin mediated recruitment of A20, a complex deubiquitinating enzyme","volume":"38","author":"Lu","year":"2013","journal-title":"Immunity"},{"key":"B24","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1186\/s13075-020-02181-4","article-title":"Synergistic activation of NF-\u03baB by TNFAIP3 (A20) reduction and UBE2L3 (UBCH7) augment that synergistically elevate lupus risk","volume":"22","author":"Kim","year":"2020","journal-title":"Arthritis Res Ther"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1016\/j.jid.2023.12.007","article-title":"A20 haploinsufficiency: A systematic review of 177 cases","volume":"144","author":"Elhani","year":"2024","journal-title":"J Invest Dermatol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2024.103722","article-title":"A20 haploinsufficiency diagnosis beyond systemic lupus erythematosus: A systematic review of the literature","volume":"24","author":"Philip","year":"2025","journal-title":"Autoimmun Rev"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-0532-1","article-title":"OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer","volume":"27","author":"Damgaard","year":"2020","journal-title":"Cell Death Differ"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2024.110292","article-title":"OTULIN-related conditions: Report of a new case and review of the literature using GenIA","volume":"265","author":"Caballero-Oteyza","year":"2024","journal-title":"Clin Immunol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e20250018","DOI":"10.70962\/jhi.20250018","article-title":"Novel genotypes, phenotypes, and triggers in humans with OTULIN haploinsufficiency","volume":"1","author":"van der Linden","year":"2025","journal-title":"J Hum Immun"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2022.2026098","article-title":"OTUD7B deubiquitinates SQSTM1\/p62 and promotes IRF3 degradation to regulate antiviral immunity","volume":"18","author":"Xie","year":"2022","journal-title":"Autophagy"},{"key":"B31","doi-asserted-by":"publisher","first-page":"9924","DOI":"10.3390\/ijms26209924","article-title":"Roles of deubiquitinases OTUD3 and OTUD5 in inflammatory bowel diseases","volume":"26","author":"Watanabe","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103287","article-title":"The deubiquitinase OTUD1 stabilizes NRF2 to alleviate hepatic ischemia\/reperfusion injury","volume":"75","author":"Zhang","year":"2024","journal-title":"Redox Biol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-025-01566-y","article-title":"OTUD1 positively regulates microglia neuroinflammation and promotes the pathogenesis of Alzheimer's disease by deubiquitinating C\/EBPbeta","volume":"46","author":"She","year":"2025","journal-title":"Acta Pharmacol Sin"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2025.103614","article-title":"Extracellular vesicle-packaged GBP2 from macrophages aggravates sepsis-induced acute lung injury by promoting ferroptosis in pulmonary vascular endothelial cells","volume":"82","author":"Li","year":"2025","journal-title":"Redox Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2206","article-title":"Phosphorylation-dependent activity of the deubiquitinase DUBA","volume":"19","author":"Huang","year":"2012","journal-title":"Nat Struct Mol Biol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-00649-z","article-title":"Deubiquitinase OTUD5 is a positive regulator of mTORC1 and mTORC2 signaling pathways","volume":"28","author":"Cho","year":"2021","journal-title":"Cell Death Differ"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00810-9","article-title":"The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NF-\u03baB signaling","volume":"19","author":"Wu","year":"2022","journal-title":"Cell Mol Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-024-02074-7","article-title":"OTUD1 deficiency alleviates LPS-induced acute lung injury in mice by reducing inflammatory response","volume":"48","author":"Zhu","year":"2024","journal-title":"Inflammation"},{"key":"B39","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1038\/s41419-022-04704-0","article-title":"Deubiquitylase OTUD3 prevents Parkinson's disease through stabilizing iron regulatory protein 2","volume":"13","author":"Jia","year":"2022","journal-title":"Cell Death Dis"},{"key":"B40","doi-asserted-by":"publisher","first-page":"5441","DOI":"10.1038\/s41467-024-49854-1","article-title":"Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury","volume":"15","author":"Zhao","year":"2024","journal-title":"Nat Commun"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/advs.201902040","article-title":"Deubiquitylase OTUD6B governs pVHL stability in an enzyme-independent manner and suppresses hepatocellular carcinoma metastasis","volume":"7","author":"Liu","year":"2020","journal-title":"Adv Sci (Weinh)"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-00971-8","article-title":"Deubiquitination of MYC by OTUB1 contributes to HK2 mediated glycolysis and breast tumorigenesis","volume":"29","author":"Han","year":"2022","journal-title":"Cell Death Differ"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-13-258","article-title":"OTUB1 promotes metastasis and serves as a marker of poor prognosis in colorectal cancer","volume":"13","author":"Zhou","year":"2014","journal-title":"Mol Cancer"},{"key":"B44","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1038\/s41392-023-01545-x","article-title":"A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block \"eat-me\" signal","volume":"8","author":"Luo","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B45","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/s12943-021-01398-4","article-title":"N(6)-methyladenosine-modified circIGF2BP3 inhibits CD8(+) T-cell responses to facilitate tumor immune evasion by promoting the deubiquitination of PD-L1 in non-small cell lung cancer","volume":"20","author":"Liu","year":"2021","journal-title":"Mol Cancer"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.62347\/jiar9649","article-title":"OTU deubiquitinases in cancer pathogenesis and precision therapy","volume":"15","author":"Yu","year":"2025","journal-title":"Am J Cancer Res"},{"key":"B47","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1007\/s13402-023-00913-7","article-title":"OTUB1 accelerates hepatocellular carcinoma by stabilizing RACK1 via its non-canonical ubiquitination","volume":"47","author":"Peng","year":"2024","journal-title":"Cell Oncol (Dordr)"},{"key":"B48","article-title":"Inhibition of OTUB2 suppresses colorectal cancer cell growth by regulating \u03b2-Catenin signaling","volume":"13","author":"Xu","year":"2023","journal-title":"Am J Cancer Res"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022110871","article-title":"The OTUD6B-LIN28B-MYC axis determines the proliferative state in multiple myeloma","volume":"41","author":"Paulmann","year":"2022","journal-title":"EMBO J"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.18632\/aging.203293","article-title":"The deubiquitinase OTUD3 stabilizes ACTN4 to drive growth and metastasis of hepatocellular carcinoma","volume":"13","author":"Xie","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"B51","doi-asserted-by":"publisher","first-page":"2116","DOI":"10.1038\/s41467-017-02029-7","article-title":"Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7","volume":"8","author":"Zhang","year":"2017","journal-title":"Nat Commun"},{"key":"B52","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41419-024-07057-y","article-title":"CircSEC24B activates autophagy and induces chemoresistance of colorectal cancer via OTUB1-mediated deubiquitination of SRPX2","volume":"15","author":"Wang","year":"2024","journal-title":"Cell Death Dis"},{"key":"B53","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1186\/s13046-020-01751-3","article-title":"OTUD7B suppresses Smac mimetic-induced lung cancer cell invasion and migration via deubiquitinating TRAF3","volume":"39","author":"Zhang","year":"2020","journal-title":"J Exp Clin Cancer Res"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-025-03647-y","article-title":"The deubiquitinase OTUD1 orchestrates cisplatin chemosensitivity of non-small cell lung cancer through destabilizing RAD23B\/XPC","volume":"44","author":"Wu","year":"2025","journal-title":"Oncogene"},{"key":"B55","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/s41419-025-08337-x","article-title":"Suppressing the OTUD7A\/KDM5B\/GABPA axis enhances the sensitivity of cisplatin through inducing ferroptosis in KRAS-mutant LUAD","volume":"17","author":"Si","year":"2025","journal-title":"Cell Death Dis"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2025.110784","article-title":"The deubiquitinase OTUD4 suppresses TAK1 kinase-dependent NF-kappaB signaling and inflammation","volume":"301","author":"Liu","year":"2025","journal-title":"J Biol Chem"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1007\/s12672-025-03022-z","article-title":"OTUB1 promotes colorectal cancer progression by stabilizing GPX4 and inhibiting ferroptosis","volume":"16","author":"Lin","year":"2025","journal-title":"Discov Oncol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/s41419-025-08017-w","article-title":"NY-ESO-1 facilitates anoikis resistance and tumor metastasis by hijacking deubiquitinase OTUB1 to stabilize PP1alpha","volume":"16","author":"Zhang","year":"2025","journal-title":"Cell Death Dis"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.09.030","article-title":"Mechanisms controlling PD-L1 expression in cancer","volume":"76","author":"Cha","year":"2019","journal-title":"Mol Cell"},{"key":"B60","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41467-023-44466-7","article-title":"Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1","volume":"15","author":"Ren","year":"2024","journal-title":"Nat Commun"},{"key":"B61","doi-asserted-by":"publisher","first-page":"e176390","DOI":"10.1172\/jci176390","article-title":"Pharmacological suppression of the OTUD4\/CD73 proteolytic axis revives antitumor immunity against immune-suppressive breast cancers","volume":"134","author":"Zhu","year":"2024","journal-title":"J Clin Invest"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2021.02.003","article-title":"OTUD5-mediated deubiquitination of YAP in macrophage promotes M2 phenotype polarization and favors triple-negative breast cancer progression","volume":"504","author":"Zhang","year":"2021","journal-title":"Cancer Lett"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2024.01.009","article-title":"Targeting MHC-I inhibitory pathways for cancer immunotherapy","volume":"45","author":"Wang","year":"2024","journal-title":"Trends Immunol"},{"key":"B64","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.3390\/cells13181596","article-title":"Overcoming antigen escape and T-cell exhaustion in CAR-T therapy for leukemia","volume":"13","author":"Bartoszewska","year":"2024","journal-title":"Cells"},{"key":"B65","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s41408-024-01193-6","article-title":"Impact of T cell characteristics on CAR-T cell therapy in hematological Malignancies","volume":"14","author":"Tao","year":"2024","journal-title":"Blood Cancer J"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00408","article-title":"Discovery of potent OTUB1\/USP8 dual inhibitors targeting proteostasis in non-small-cell lung cancer","volume":"65","author":"Tan","year":"2022","journal-title":"J Med Chem"},{"key":"B67","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/s41419-023-05900-2","article-title":"Discovery of an OTUD3 inhibitor for the treatment of non-small cell lung cancer","volume":"14","author":"Zhang","year":"2023","journal-title":"Cell Death Dis"},{"key":"B68","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.tim.2021.04.002","article-title":"Ovarian tumor domain proteases in pathogen infection","volume":"30","author":"Schl\u00fcter","year":"2022","journal-title":"Trends Microbiol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"517","DOI":"10.3390\/cancers15020517","article-title":"AtomNet-aided OTUD7B inhibitor discovery and validation","volume":"15","author":"Chen","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B70","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/s42004-025-01410-8","article-title":"Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation","volume":"8","author":"Vuorinen","year":"2025","journal-title":"Commun Chem"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.10.020","article-title":"Blockade of deubiquitinase YOD1 degrades oncogenic PML\/RAR\u03b1 and eradicates acute promyelocytic leukemia cells","volume":"12","author":"Shao","year":"2022","journal-title":"Acta Pharm Sin B"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1042\/bcj20230119","article-title":"Development of an OTUD1 ubiquitin variant inhibitor","volume":"480","author":"Liu","year":"2023","journal-title":"Biochem J"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c02975","article-title":"Deubiquitinase-targeting chimeras (DUBTACs) as a potential paradigm-shifting drug discovery approach","volume":"68","author":"Ma","year":"2025","journal-title":"J Med Chem"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.13345\/j.cjb.250348","article-title":"Advances in deubiquitinase-targeting chimera technology for anticancer drug development","volume":"41","author":"Ruan","year":"2025","journal-title":"Sheng Wu Gong Cheng Xue Bao"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c06306","article-title":"Deubiquitinase-targeting chimeras mediated stabilization of tumor suppressive E3 ligase proteins as a strategy for cancer therapy","volume":"147","author":"Chen","year":"2025","journal-title":"J Am Chem Soc"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.10.009","article-title":"Ubiquitin binding to A20 ZnF4 is required for modulation of NF-kappaB signaling","volume":"40","author":"Bosanac","year":"2010","journal-title":"Mol Cell"},{"key":"B77","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/978-1-0716-1665-9_5","article-title":"Mechanistic and structural features of PROTAC ternary complexes","volume":"2365","author":"Casement","year":"2021","journal-title":"Methods Mol Biol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1016\/j.cmet.2022.05.005","article-title":"Deubiquitinase OTUD3 regulates metabolism homeostasis in response to nutritional stresses","volume":"34","author":"Zhou","year":"2022","journal-title":"Cell Metab"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1385","article-title":"OTUB1 inhibits breast cancer by non-canonically stabilizing CCN6","volume":"13","author":"Zhao","year":"2023","journal-title":"Clin Transl Med"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2025.01.035","article-title":"Ailanthone induces triple-negative breast cancer cells death involving the inhibition of OTUB1-mediated ERR\u03b1 deubiquitylation","volume":"77","author":"Zhang","year":"2025","journal-title":"J Adv Res"},{"key":"B81","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/s41388-022-02537-x","article-title":"CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1","volume":"42","author":"Li","year":"2023","journal-title":"Oncogene"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020005199","article-title":"Targeting the Otub1\/c-Maf axis for the treatment of multiple myeloma","volume":"137","author":"Xu","year":"2021","journal-title":"Blood"},{"key":"B83","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/s41419-024-07185-5","article-title":"OTUB1 regulation of ferroptosis and the protective role of ferrostatin-1 in lupus nephritis","volume":"15","author":"Liu","year":"2024","journal-title":"Cell Death Dis"},{"key":"B84","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1186\/s12951-022-01536-0","article-title":"Immune-regulating strategy against rheumatoid arthritis by inducing tolerogenic dendritic cells with modified zinc peroxide nanoparticles","volume":"20","author":"Qiao","year":"2022","journal-title":"J Nanobiotechnol"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101989","article-title":"ERK\/RSK-mediated phosphorylation of Y-box binding protein-1 aggravates diabetic cardiomyopathy by suppressing its interaction with deubiquitinase OTUB1","volume":"298","author":"Zhong","year":"2022","journal-title":"J Biol Chem"},{"key":"B86","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/s41388-021-02071-2","article-title":"Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis","volume":"41","author":"Yu","year":"2022","journal-title":"Oncogene"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2017.02.011","article-title":"Ovarian tumor domain-containing protein 1 deubiquitinates and stabilizes p53","volume":"33","author":"Piao","year":"2017","journal-title":"Cell Signal"},{"key":"B88","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1038\/s41420-022-01119-w","article-title":"Deubiquitylase OTUD1 confers Erlotinib sensitivity in non-small cell lung cancer through inhibition of nuclear translocation of YAP1","volume":"8","author":"Liu","year":"2022","journal-title":"Cell Death Discov"},{"key":"B89","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1186\/s13046-023-02781-3","article-title":"Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis","volume":"42","author":"Han","year":"2023","journal-title":"J Exp Clin Cancer Res"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1038\/s44319-024-00276-6","article-title":"YOD1 sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2","volume":"25","author":"Shen","year":"2024","journal-title":"EMBO Rep"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2023.155243","article-title":"Leonurine alleviates rheumatoid arthritis by regulating the Hippo signaling pathway","volume":"123","author":"Ma","year":"2024","journal-title":"Phytomedicine"},{"key":"B92","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1186\/s12885-020-07069-9","article-title":"Tumor suppressor OTUD3 induces growth inhibition and apoptosis by directly deubiquitinating and stabilizing p53 in invasive breast carcinoma cells","volume":"20","author":"Pu","year":"2020","journal-title":"BMC Cancer"},{"key":"B93","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/s41419-024-06526-8","article-title":"Phosphorylation-dependent deubiquitinase OTUD3 regulates YY1 stability and promotes colorectal cancer progression","volume":"15","author":"Wu","year":"2024","journal-title":"Cell Death Dis"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-0571-7","article-title":"Ubiquitin ligase CHIP regulates OTUD3 stability and suppresses tumour metastasis in lung cancer","volume":"27","author":"Zhang","year":"2020","journal-title":"Cell Death Differ"},{"key":"B95","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1186\/s12964-024-01519-8","article-title":"Rolapitant treats lung cancer by targeting deubiquitinase OTUD3","volume":"22","author":"Du","year":"2024","journal-title":"Cell Commun Signal"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.115681","article-title":"OTUD4 inhibits ferroptosis by stabilizing GPX4 and suppressing autophagic degradation to promote tumor progression","volume":"44","author":"Chen","year":"2025","journal-title":"Cell Rep"},{"key":"B97","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13062-024-00475-0","article-title":"OTUD5 promotes the growth of hepatocellular carcinoma by deubiquitinating and stabilizing SLC38A1","volume":"19","author":"Yang","year":"2024","journal-title":"Biol Direct"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-01036-6","article-title":"Deubiquitinase OTUD6A promotes breast cancer progression by increasing TopBP1 stability and rendering tumor cells resistant to DNA-damaging therapy","volume":"29","author":"Zhao","year":"2022","journal-title":"Cell Death Differ"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-023-01148-7","article-title":"Deubiquitinase OTUD6A in macrophages promotes intestinal inflammation and colitis via deubiquitination of NLRP3","volume":"30","author":"Liu","year":"2023","journal-title":"Cell Death Differ"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-00960-x","article-title":"Prostate-specific oncogene OTUD6A promotes prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc","volume":"29","author":"Peng","year":"2022","journal-title":"Cell Death Differ"},{"key":"B101","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1093\/ecco-jcc\/jjaa131","article-title":"ABIN3 negatively regulates necroptosis-induced intestinal inflammation through recruiting A20 and restricting the ubiquitination of RIPK3 in inflammatory bowel disease","volume":"15","author":"Zhou","year":"2021","journal-title":"J Crohns Colitis"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.155482","article-title":"Ophiopogonin D alleviates acute lung injury by regulating inflammation via the STAT3\/A20\/ASK1 axis","volume":"130","author":"Shen","year":"2024","journal-title":"Phytomedicine"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202004846","article-title":"SPOP and OTUD7A control EWS-FLI1 protein stability to govern Ewing sarcoma growth","volume":"8","author":"Su","year":"2021","journal-title":"Adv Sci (Weinh)"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202004504","article-title":"OTUD7B deubiquitinates LSD1 to govern its binding partner specificity, homeostasis, and breast cancer metastasis","volume":"8","author":"Gong","year":"2021","journal-title":"Adv Sci (Weinh)"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs-152461\/v1","article-title":"Deubiquitinase ZRANB1 drives hepatocellular carcinoma progression through SP1-LOXL2 axis","volume":"11","author":"Li","year":"2021","journal-title":"Am J Cancer Res"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.155969","article-title":"Targeting and degradation of OTUB1 by Erianin for antimetastasis in esophageal squamous cell carcinoma","volume":"135","author":"Zhu","year":"2024","journal-title":"Phytomedicine"},{"key":"B107","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/s41419-024-06941-x","article-title":"Rupatadine-inhibited OTUD3 promotes DLBCL progression and immune evasion through deubiquitinating MYL12A and PD-L1","volume":"15","author":"Sui","year":"2024","journal-title":"Cell Death Dis"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202301852","article-title":"Deubiquitinase OTUD5 as a novel protector against 4-HNE-triggered ferroptosis in myocardial ischemia\/reperfusion injury","volume":"10","author":"Liu","year":"2023","journal-title":"Adv Sci (Weinh)"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1843621\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T08:26:02Z","timestamp":1782894362000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1843621\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":108,"alternative-id":["10.3389\/fimmu.2026.1843621"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1843621","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]},"article-number":"1843621"}}