{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T09:01:14Z","timestamp":1784797274690,"version":"3.55.0"},"reference-count":130,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Ubiquitin-specific protease 25 (USP25), a pivotal deubiquitinating enzyme, has attracted increasing attention in cardiovascular and cerebrovascular research due to its regulatory function in maintaining ubiquitination homeostasis. Considerable advances have been achieved in elucidating the molecular mechanisms through which USP25 participates in the pathological progression of diverse cardiovascular and cerebrovascular disorders. From the perspective of translational medicine, notable progress has also been observed in the development of USP25-targeted therapeutics, with several inhibitors having advanced to preclinical and early-phase clinical trials, thereby offering promising targets for precision treatment. Nevertheless, a systematic synthesis of fundamental biological properties, the trajectory of research development, and the intricate upstream\u2013downstream regulatory networks of USP25, together with its mechanistic roles and therapeutic potential in these diseases, remains absent. In response, this review provides an in-depth summary of the essential biological features of USP25, elucidates the interplay between its upstream regulators and downstream substrates, and highlights its specific molecular mechanisms in cardiovascular and cerebrovascular disease pathogenesis. Additionally, the feasibility and strategic approaches of targeting USP25 for therapeutic purposes are analyzed, while the limitations and potential breakthroughs in the development of USP25 inhibitors are discussed. Finally, priority research directions are proposed to guide future exploration, with the ultimate aim of contributing theoretical foundations and novel perspectives for clinical management of cardiovascular and cerebrovascular diseases.<\/jats:p>","DOI":"10.3389\/fcell.2026.1802539","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T08:07:34Z","timestamp":1784794054000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ubiquitin-specific protease 25: a new regulator for cardiovascular and cerebrovascular diseases"],"prefix":"10.3389","volume":"14","author":[{"given":"Yingchun","family":"Shao","sequence":"first","affiliation":[{"name":"Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital)","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital)","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhai","sequence":"additional","affiliation":[{"name":"Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital)","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fusheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital)","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.molcel.2024.12.015","article-title":"Ubiquitin-A structural perspective","volume":"85","author":"Agrata","year":"2025","journal-title":"Mol. Cell."},{"key":"B2","doi-asserted-by":"publisher","first-page":"120425","DOI":"10.1016\/j.lfs.2022.120425","article-title":"Altered gene expression levels of IL-17\/TRAF6\/MAPK\/USP25 axis and pro-inflammatory cytokine levels in lung tissue of obese ovalbumin-sensitized rats","volume":"296","author":"Aslani","year":"2022","journal-title":"Life Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2655","DOI":"10.3390\/cells11172655","article-title":"Differential epigenetic status and responses to stressors between retinal cybrids cells with African versus European mitochondrial DNA: insights into disease susceptibilities","volume":"11","author":"Atilano","year":"2022","journal-title":"Cells"},{"key":"B4","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1038\/s41420-024-02264-0","article-title":"USP39 regulates pyruvate handling in non-small cell lung cancer","volume":"10","author":"Becirovic","year":"2024","journal-title":"Cell. Death Discov."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e36542","DOI":"10.1371\/journal.pone.0036542","article-title":"Ubiquitin-specific protease 25 functions in endoplasmic Reticulum-associated degradation","volume":"7","author":"Blount","year":"2012","journal-title":"PLoS One"},{"key":"B6","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1007\/s00018-005-5533-1","article-title":"The ubiquitin-specific protease USP25 interacts with three sarcomeric proteins","volume":"63","author":"Bosch-Comas","year":"2006","journal-title":"Cell. Mol. Life Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2344","DOI":"10.1056\/NEJMra1706537","article-title":"Down syndrome","volume":"382","author":"Bull","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1089\/ars.2020.8110","article-title":"Vascular extracellular matrix remodeling and hypertension","volume":"34","author":"Cai","year":"2021","journal-title":"Antioxid. Redox Signal"},{"key":"B9","doi-asserted-by":"publisher","first-page":"3648","DOI":"10.1038\/s41467-023-39412-6","article-title":"USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice","volume":"14","author":"Cai","year":"","journal-title":"Nat. Commun."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e22971","DOI":"10.1096\/fj.202300057R","article-title":"USP25 contributes to defective neurogenesis and cognitive impairments","volume":"37","author":"Cai","year":"","journal-title":"FASEB J."},{"key":"B11","doi-asserted-by":"publisher","first-page":"347","DOI":"10.3892\/mmr.2022.12863","article-title":"Downregulation of deubiquitinating enzyme USP25 promotes the development of allergic rhinitis by enhancing TSLP signaling in the nasal epithelium","volume":"26","author":"Chang","year":"2022","journal-title":"Mol. Med. Rep."},{"key":"B12","doi-asserted-by":"publisher","first-page":"4546","DOI":"10.3390\/ijms22094546","article-title":"Advances in the development ubiquitin-specific peptidase (USP) inhibitors","volume":"22","author":"Chen","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1016\/j.apsb.2024.12.033","article-title":"USP25 ameliorates vascular remodeling by deubiquitinating FOXO3 and promoting autophagic degradation of FOXO3","volume":"15","author":"Chen","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"B14","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.canlet.2018.11.013","article-title":"Inhibition of tankyrase by a novel small molecule significantly attenuates prostate cancer cell proliferation","volume":"443","author":"Cheng","year":"2019","journal-title":"Cancer Lett."},{"key":"B15","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/j.yexcr.2009.10.023","article-title":"Functional interaction between the ubiquitin-specific protease 25 and the SYK tyrosine kinase","volume":"316","author":"Cholay","year":"2010","journal-title":"Exp. Cell. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e134","DOI":"10.1093\/labmed\/lmac010","article-title":"A novel USP25::PDGFRA gene fusion in a 78 year old patient with a myeloid neoplasm","volume":"53","author":"Dalland","year":"2022","journal-title":"Lab. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41392-020-0107-0","article-title":"The role of ubiquitination in tumorigenesis and targeted drug discovery","volume":"5","author":"Deng","year":"2020","journal-title":"Signal Transduct. Target Ther."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e5571","DOI":"10.1371\/journal.pone.0005571","article-title":"The UBA-UIM domains of the USP25 regulate the enzyme ubiquitination state and modulate substrate recognition","volume":"4","author":"Denuc","year":"2009","journal-title":"PLoS One"},{"key":"B19","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/s41580-022-00543-1","article-title":"An expanded lexicon for the ubiquitin code","volume":"24","author":"Dikic","year":"2023","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1139\/cjpp-2016-0303","article-title":"Chloroquine attenuates lipopolysaccharide-induced inflammatory responses through upregulation of USP25","volume":"95","author":"Ding","year":"2017","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"19951","DOI":"10.1002\/jcp.28593","article-title":"The miR-27a-3p\/USP25 axis participates in the pathogenesis of recurrent miscarriage by inhibiting trophoblast migration and invasion","volume":"234","author":"Ding","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"104930","DOI":"10.1016\/j.cellimm.2025.104930","article-title":"Tim-3 promotes viral infection by suppressing the USP25-TRAF3-IRF7 signaling pathway","author":"Du","year":"2025","journal-title":"Cell. Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1093\/infdis\/jiae352","article-title":"USP25 promotes the antimycobacterial response of macrophages through stabilizing B-Raf and C-Raf","volume":"231","author":"Fu","year":"2025","journal-title":"J. Infect. Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1002\/cbin.11775","article-title":"USP25 inhibits DNA damage by stabilizing BARD1 protein in a house dust mite-induced asthmatic model in vitro and in vivo","volume":"46","author":"Gan","year":"2022","journal-title":"Cell. Biol. Int."},{"key":"B25","doi-asserted-by":"publisher","first-page":"779718","DOI":"10.3389\/fcell.2021.779718","article-title":"USP25 regulates the proliferation and apoptosis of ovarian granulosa cells in polycystic ovary syndrome by modulating the PI3K\/AKT pathway via deubiquitinating PTEN","volume":"9","author":"Gao","year":"2021","journal-title":"Front. Cell. Dev. Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.molcel.2019.02.030","article-title":"Distinct USP25 and USP28 oligomerization states regulate deubiquitinating activity","volume":"74","author":"Gersch","year":"2019","journal-title":"Mol. Cell."},{"key":"B27","doi-asserted-by":"publisher","first-page":"3497","DOI":"10.1007\/s00018-016-2255-5","article-title":"The recognition of ubiquitinated proteins by the proteasome","volume":"73","author":"Grice","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"10466","DOI":"10.1074\/jbc.RA118.003021","article-title":"Usp25m protease regulates ubiquitin-like processing of TUG proteins to control GLUT4 glucose transporter translocation in adipocytes","volume":"293","author":"Habtemichael","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"6236","DOI":"10.7150\/thno.99340","article-title":"Cardiomyocyte-derived USP28 negatively regulates antioxidant response and promotes cardiac hypertrophy via deubiquitinating TRIM21","volume":"14","author":"Han","year":"2024","journal-title":"Theranostics"},{"key":"B30","doi-asserted-by":"publisher","first-page":"5294","DOI":"10.1172\/JCI98287","article-title":"Inadequate ubiquitination-proteasome coupling contributes to myocardial ischemia-reperfusion injury","volume":"128","author":"Hu","year":"2018","journal-title":"J. Clin. Invest."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1007\/s10753-024-01991-x","article-title":"A new modulator of neuroinflammation in diabetic retinopathy: USP25","volume":"47","author":"Hu","year":"2024","journal-title":"Inflammation"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2958","DOI":"10.1007\/s12010-024-05148-2","article-title":"Long noncoding RNA SNHG12 regulates ischemia\/reperfusion (I\/R)-mediated Acute Kidney Injury (AKI) through miR-129-1-3p\/Ubiquitin specific peptidase 25 axis","volume":"197","author":"Huang","year":"2025","journal-title":"Appl. Biochem. Biotechnol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2627","DOI":"10.1038\/s41467-024-45977-7","article-title":"Expression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease","volume":"15","author":"Jiang","year":"2024","journal-title":"Nat. Commun."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1038\/s41418-025-01444-4","article-title":"USP25 directly interacts with and deubiquitinates PPARalpha to increase PPARalpha stability in hepatocytes and attenuate high-fat diet-induced MASLD in mice","volume":"32","author":"Jin","year":"2025","journal-title":"Cell. Death Differ."},{"key":"B35","doi-asserted-by":"publisher","first-page":"465","DOI":"10.3390\/biology12030465","article-title":"Antineoplastic nature of WWOX in glioblastoma is mainly a consequence of reduced cell viability and invasion","volume":"12","author":"Kaluzinska-Kolat","year":"2023","journal-title":"Biol. (Basel)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"45037","DOI":"10.1038\/srep45037","article-title":"Tandem UIMs confer Lys48 ubiquitin chain substrate preference to deubiquitinase USP25","volume":"7","author":"Kawaguchi","year":"2017","journal-title":"Sci. Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1128\/MCB.01325-14","article-title":"Vaccinia-related kinase 2 controls the stability of the eukaryotic chaperonin TRiC\/CCT by inhibiting the deubiquitinating enzyme USP25","volume":"35","author":"Kim","year":"2015","journal-title":"Mol. Cell. Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41588-023-01584-8","article-title":"Multi-ancestry genome-wide association meta-analysis of Parkinson's disease","volume":"56","author":"Kim","year":"2024","journal-title":"Nat. Genet."},{"key":"B39","doi-asserted-by":"publisher","first-page":"41","DOI":"10.3389\/fnagi.2018.00041","article-title":"MicroRNA-455-3p as a potential biomarker for Alzheimer's disease: an update","volume":"10","author":"Kumar","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"467","DOI":"10.3390\/biom12030467","article-title":"Acetylation, phosphorylation, ubiquitination (oh my!): following post-translational modifications on the ubiquitin road","volume":"12","author":"Lacoursiere","year":"2022","journal-title":"Biomolecules"},{"key":"B41","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1186\/s12964-025-02123-0","article-title":"Ubiquitin-specific protease: an emerging key player in cardiomyopathy","volume":"23","author":"Li","year":"2025","journal-title":"Cell. Commun. Signal"},{"key":"B42","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1186\/1476-4598-13-166","article-title":"miRNA-200c inhibits invasion and metastasis of human non-small cell lung cancer by directly targeting ubiquitin specific peptidase 25","volume":"13","author":"Li","year":"2014","journal-title":"Mol. Cancer"},{"key":"B43","doi-asserted-by":"publisher","first-page":"851","DOI":"10.3390\/cells11050851","article-title":"Ubiquitination-Proteasome System (UPS) and autophagy two main protein degradation machineries in response to cell stress","volume":"11","author":"Li","year":"2022","journal-title":"Cells"},{"key":"B44","doi-asserted-by":"publisher","first-page":"109917","DOI":"10.1016\/j.intimp.2023.109917","article-title":"USP25 deficiency promotes T cell dysfunction and transplant acceptance via mitochondrial dynamics","volume":"117","author":"Li","year":"","journal-title":"Int. Immunopharmacol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.3233\/JAD-221184","article-title":"Regulation of USP25 by SP1 associates with amyloidogenesis","volume":"92","author":"Li","year":"","journal-title":"J. Alzheimers Dis."},{"key":"B46","doi-asserted-by":"publisher","first-page":"e2301641","DOI":"10.1002\/advs.202301641","article-title":"USP25 inhibits neuroinflammatory responses after cerebral ischemic stroke by deubiquitinating TAB2","volume":"10","author":"Li","year":"","journal-title":"Adv. Sci. (Weinh)"},{"key":"B47","doi-asserted-by":"publisher","first-page":"e2403485","DOI":"10.1002\/advs.202403485","article-title":"USP25 elevates SHLD2-Mediated DNA double-strand break repair and regulates chemoresponse in cancer","volume":"11","author":"Li","year":"2024","journal-title":"Adv. Sci. (Weinh)"},{"key":"B48","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1186\/s12866-025-04035-y","article-title":"Effects of USP25 knockout on the gut microbial diversity and composition in mice","volume":"25","author":"Li","year":"2025","journal-title":"BMC Microbiol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"11324","DOI":"10.1073\/pnas.1509968112","article-title":"Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6","volume":"112","author":"Lin","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B50","doi-asserted-by":"publisher","first-page":"4973","DOI":"10.1038\/s41467-018-07510-5","article-title":"A quaternary tetramer assembly inhibits the deubiquitinating activity of USP25","volume":"9","author":"Liu","year":"2018","journal-title":"Nat. Commun."},{"key":"B51","doi-asserted-by":"publisher","first-page":"806850","DOI":"10.3389\/fcell.2021.806850","article-title":"Ubiquitin-specific protease 25 aggravates acute pancreatitis and acute pancreatitis-related multiple organ injury by destroying tight junctions through activation of the STAT3 pathway","volume":"9","author":"Liu","year":"2021","journal-title":"Front. Cell. Dev. Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1016\/j.jcmgh.2022.07.013","article-title":"USP25 deficiency exacerbates acute pancreatitis via Up-Regulating TBK1-NF-kappaB signaling in macrophages","volume":"14","author":"Liu","year":"2022","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"110877","DOI":"10.1016\/j.intimp.2023.110877","article-title":"USP25 ameliorates diabetic nephropathy by inhibiting TRAF6-mediated inflammatory responses","volume":"124","author":"Liu","year":"","journal-title":"Int. Immunopharmacol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"2229","DOI":"10.1097\/CM9.0000000000002714","article-title":"USP25 promotes hepatocellular carcinoma progression by interacting with TRIM21 via the Wnt\/beta-catenin signaling pathway","volume":"136","author":"Liu","year":"","journal-title":"Chin. Med. J. Engl."},{"key":"B55","doi-asserted-by":"publisher","first-page":"107876","DOI":"10.1016\/j.jbc.2024.107876","article-title":"Ubiquitin-specific peptidase 25 ameliorates hepatic steatosis by stabilizing peroxisome proliferator-activated receptor alpha","volume":"300","author":"Liu","year":"2024","journal-title":"J. Biol. Chem."},{"key":"B56","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41419-024-07315-z","article-title":"Ubiquitin-specific protease 25 ameliorates ulcerative colitis by regulating the degradation of phosphor-STAT3","volume":"16","author":"Liu","year":"2025","journal-title":"Cell. Death Dis."},{"key":"B57","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1016\/j.bbagrm.2018.08.001","article-title":"LPS promotes HBO1 stability via USP25 to modulate inflammatory gene transcription in THP-1 cells","volume":"1861","author":"Long","year":"2018","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech."},{"key":"B58","doi-asserted-by":"publisher","first-page":"L252","DOI":"10.1152\/ajplung.00142.2019","article-title":"Cigarette smoke extract modulates Pseudomonas aeruginosa bacterial load via USP25\/HDAC11 axis in lung epithelial cells","volume":"318","author":"Long","year":"2020","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1097\/SHK.0000000000001992","article-title":"Usp25 upregulation boosts gsdmd -Mediated pyroptosis of acinar cells in acute pancreatitis","volume":"58","author":"Lv","year":"2022","journal-title":"Shock"},{"key":"B60","doi-asserted-by":"publisher","first-page":"110337","DOI":"10.1016\/j.jbc.2025.110337","article-title":"USP25 maintains KRAS expression and inhibiting the deubiquitinase suppresses KRAS signaling in human cancer","volume":"301","author":"Ma","year":"2025","journal-title":"J. Biol. Chem."},{"key":"B61","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/j.molcel.2008.03.021","article-title":"Mechanism and consequences for paralog-specific sumoylation of ubiquitin-specific protease 25","volume":"30","author":"Meulmeester","year":"2008","journal-title":"Mol. Cell."},{"key":"B62","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1016\/j.molcel.2008.05.010","article-title":"SUMO takes control of a ubiquitin-specific protease","volume":"30","author":"Mohideen","year":"2008","journal-title":"Mol. Cell."},{"key":"B63","doi-asserted-by":"publisher","first-page":"2504738","DOI":"10.1080\/21688370.2025.2504738","article-title":"Deubiquitinating enzymes at the crossroads of blood-brain barrier integrity and neurodegeneration: mechanistic insights, therapeutic targeting and future directions","volume":"14","author":"Munavar","year":"2026","journal-title":"Tissue Barriers"},{"key":"B64","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s41569-018-0007-y","article-title":"Mechanisms of physiological and pathological cardiac hypertrophy","volume":"15","author":"Nakamura","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"2070","DOI":"10.1038\/s41467-022-29684-9","article-title":"USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer","volume":"13","author":"Nelson","year":"2022","journal-title":"Nat. Commun."},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.3390\/biom10111548","article-title":"USP25 regulates EGFR fate by modulating EGF-induced ubiquitylation dynamics","volume":"10","author":"Nino","year":"2020","journal-title":"Biomolecules"},{"key":"B67","doi-asserted-by":"publisher","first-page":"2950","DOI":"10.1038\/s44319-024-00167-w","article-title":"Structural basis for the bi-specificity of USP25 and USP28 inhibitors","volume":"25","author":"Patzke","year":"2024","journal-title":"EMBO Rep."},{"key":"B68","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1038\/nm.3739","article-title":"Ubiquitination in disease pathogenesis and treatment","volume":"20","author":"Popovic","year":"2014","journal-title":"Nat. Med."},{"key":"B69","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1142\/S0192415X25500193","article-title":"Ophiopogonin D from ophiopogon japonicas-induced USP25 activity to reduce ferroptosis of macrophage in acute lung injury by the inhibition of bound Rac1 and Nox1 complex","volume":"53","author":"Pu","year":"2025","journal-title":"Am. J. Chin. Med."},{"key":"B70","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.bbrc.2018.03.015","article-title":"Smurf1 restricts the antiviral function mediated by USP25 through promoting its ubiquitination and degradation","volume":"498","author":"Qian","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B71","doi-asserted-by":"publisher","first-page":"13206","DOI":"10.1074\/jbc.M116.718080","article-title":"The type I Interferon-IRF7 axis mediates transcriptional expression of Usp25 gene","volume":"291","author":"Ren","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B72","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/j.ahj.2015.08.005","article-title":"Reperfusion therapy for acute myocardial infarction: concepts and controversies from inception to acceptance","volume":"170","author":"Rentrop","year":"2015","journal-title":"Am. Heart J."},{"key":"B73","doi-asserted-by":"publisher","first-page":"e71596","DOI":"10.7554\/eLife.71596","article-title":"USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma","volume":"10","author":"Ruiz","year":"2021","journal-title":"Elife"},{"key":"B74","doi-asserted-by":"publisher","first-page":"4710","DOI":"10.1038\/s41598-019-40596-5","article-title":"The deubiquitinating enzyme USP25 binds tankyrase and regulates trafficking of the facilitative glucose transporter GLUT4 in adipocytes","volume":"9","author":"Sadler","year":"2019","journal-title":"Sci. Rep."},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1101\/2025.01.27.635188","article-title":"Targeting deubiquitinating enzymes (DUBs) and ubiquitin pathway modulators to enhance host defense against bacterial infections","author":"Santelices","year":"","journal-title":"bioRxiv"},{"key":"B76","doi-asserted-by":"publisher","first-page":"e0031225","DOI":"10.1128\/mbio.00312-25","article-title":"Targeting deubiquitinating enzymes and ubiquitin pathway modulators to enhance host defense against bacterial infections","volume":"16","author":"Santelices","year":"","journal-title":"mBio"},{"key":"B77","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.molcel.2019.02.029","article-title":"Differential oligomerization of the deubiquitinases USP25 and USP28 regulates their activities","volume":"74","author":"Sauer","year":"2019","journal-title":"Mol. Cell."},{"key":"B78","doi-asserted-by":"publisher","first-page":"866","DOI":"10.3238\/arztebl.2010.0866","article-title":"End organ damage in hypertension","volume":"107","author":"Schmieder","year":"2010","journal-title":"Dtsch. Arztebl Int."},{"key":"B79","doi-asserted-by":"publisher","first-page":"124296","DOI":"10.1016\/j.ijbiomac.2023.124296","article-title":"MST1: a future novel target for cardiac diseases","volume":"239","author":"Shao","year":"","journal-title":"Int. J. Biol. Macromol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.cytogfr.2023.06.007","article-title":"Growth differentiation factor 11: a new hope for the treatment of cardiovascular diseases","volume":"71","author":"Shao","year":"","journal-title":"Cytokine Growth Factor Rev."},{"key":"B81","doi-asserted-by":"publisher","first-page":"100997","DOI":"10.1016\/j.jpha.2024.100997","article-title":"miR-135b: an emerging player in cardio-cerebrovascular diseases","volume":"14","author":"Shao","year":"2024","journal-title":"J. Pharm. Anal."},{"key":"B82","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1007\/s12104-013-9495-1","article-title":"(1)H, (1)(3)C and (1)(5)N backbone and side-chain resonance assignments of the N-terminal ubiquitin-binding domains of USP25","volume":"8","author":"Shi","year":"2014","journal-title":"Biomol. NMR Assign."},{"key":"B83","doi-asserted-by":"publisher","first-page":"3867","DOI":"10.1038\/s41388-020-1253-0","article-title":"Deubiquitylase USP25 prevents degradation of BCR-ABL protein and ensures proliferation of Ph-positive leukemia cells","volume":"39","author":"Shibata","year":"2020","journal-title":"Oncogene"},{"key":"B84","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.yjmcc.2016.06.001","article-title":"Physiological and pathological cardiac hypertrophy","volume":"97","author":"Shimizu","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"106213","DOI":"10.1016\/j.ebiom.2026.106213","article-title":"USP25 regulates atherosclerosis by restricting RIPK1-mediated inflammatory responses","volume":"126","author":"Su","year":"2026","journal-title":"EBioMedicine"},{"key":"B86","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1186\/s13018-023-04083-y","article-title":"Ubiquitin-specific peptidase 25 exacerbated osteoarthritis progression through facilitating TXNIP ubiquitination and NLRP3 inflammasome activation","volume":"18","author":"Sui","year":"2023","journal-title":"J. Orthop. Surg. Res."},{"key":"B87","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1186\/s12951-025-03671-w","article-title":"Engineered MEVs for photoreceptor-targeted delivery of USP25 to alleviate diabetic retinopathy","volume":"23","author":"Sun","year":"2025","journal-title":"J. Nanobiotechnology"},{"key":"B88","doi-asserted-by":"publisher","first-page":"9087190","DOI":"10.1155\/2022\/9087190","article-title":"Deubiquitination of TNKS1 regulates Wnt\/beta-catenin to affect the expression of USP25 to promote the progression of glioma","volume":"2022","author":"Tang","year":"2022","journal-title":"Dis. Markers"},{"key":"B89","doi-asserted-by":"publisher","first-page":"2495","DOI":"10.1016\/j.devcel.2023.08.013","article-title":"Usp25-Erlin1\/2 activity limits cholesterol flux to restrict virus infection","volume":"58","author":"Teo","year":"2023","journal-title":"Dev. Cell."},{"key":"B90","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1006\/geno.1999.6025","article-title":"USP25, a novel gene encoding a deubiquitinating enzyme, is located in the gene-poor region 21q11.2","volume":"62","author":"Valero","year":"1999","journal-title":"Genomics"},{"key":"B91","doi-asserted-by":"publisher","first-page":"RESEARCH0043","DOI":"10.1186\/gb-2001-2-10-research0043","article-title":"Characterization of alternatively spliced products and tissue-specific isoforms of USP28 and USP25","volume":"2","author":"Valero","year":"2001","journal-title":"Genome Biol."},{"key":"B92","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/s41419-017-0208-z","article-title":"Targeting deubiquitinase USP28 for cancer therapy","volume":"9","author":"Wang","year":"2018","journal-title":"Cell. Death Dis."},{"key":"B93","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/s43018-020-0089-4","article-title":"The deubiquitinase USP25 supports colonic inflammation and bacterial infection and promotes colorectal cancer","volume":"1","author":"Wang","year":"2020","journal-title":"Nat. Cancer"},{"key":"B94","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1111\/febs.15461","article-title":"USP28 and USP25 are downregulated by vismodegib in vitro and in colorectal cancer cell lines","volume":"288","author":"Wang","year":"2021","journal-title":"FEBS J."},{"key":"B95","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/s41418-024-01426-y","article-title":"USP19 potentiates autophagic cell death via inhibiting mTOR pathway through deubiquitinating NEK9 in pancreatic cancer","volume":"32","author":"Wang","year":"","journal-title":"Cell. Death Differ."},{"key":"B96","doi-asserted-by":"publisher","first-page":"e70118","DOI":"10.1111\/cbdd.70118","article-title":"The transfer of USP25 by exosomes of adipose tissue-derived mesenchymal stem cells ameliorates diabetic nephropathy through stabilizing SMAD7 expression","volume":"105","author":"Wang","year":"","journal-title":"Chem. Biol. Drug Des."},{"key":"B97","doi-asserted-by":"publisher","first-page":"13754","DOI":"10.1021\/jacs.5c01889","article-title":"USP28-Based deubiquitinase-targeting chimeras for cancer treatment","volume":"147","author":"Wang","year":"","journal-title":"J. Am. Chem. Soc."},{"key":"B98","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.molimm.2018.12.017","article-title":"USP25 promotes endotoxin tolerance via suppressing K48-linked ubiquitination and degradation of TRAF3 in kupffer cells","volume":"106","author":"Wen","year":"2019","journal-title":"Mol. Immunol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"3113","DOI":"10.1021\/acschembio.7b00334","article-title":"Identification and characterization of dual inhibitors of the USP25\/28 deubiquitinating enzyme subfamily","volume":"12","author":"Wrigley","year":"2017","journal-title":"ACS Chem. Biol."},{"key":"B100","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1038\/s41401-022-01041-y","article-title":"GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy","volume":"44","author":"Wu","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"B101","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1161\/CIRCULATIONAHA.123.065603","article-title":"USP28 serves as a key suppressor of mitochondrial morphofunctional defects and cardiac dysfunction in the diabetic heart","volume":"149","author":"Xie","year":"2024","journal-title":"Circulation"},{"key":"B102","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1101\/gad.300889.117","article-title":"USP25 regulates Wnt signaling by controlling the stability of tankyrases","volume":"31","author":"Xu","year":"2017","journal-title":"Genes. Dev."},{"key":"B103","doi-asserted-by":"publisher","first-page":"e1010299","DOI":"10.1371\/journal.ppat.1010299","article-title":"MicroRNA-200c-targeted contactin 1 facilitates the replication of influenza A virus by accelerating the degradation of MAVS","volume":"18","author":"Xu","year":"","journal-title":"PLoS Pathog."},{"key":"B104","doi-asserted-by":"publisher","first-page":"569","DOI":"10.4149\/gpb_2022038","article-title":"Ubiquitin specific peptidase 25 alleviates acute lung injury and suppresses the inflammatory response in lung epithelial cells","volume":"41","author":"Xu","year":"","journal-title":"Gen. Physiol. Biophys."},{"key":"B105","doi-asserted-by":"publisher","first-page":"115746","DOI":"10.1016\/j.bcp.2023.115746","article-title":"Otilonium bromide acts as a selective USP28 inhibitor and exhibits cytotoxic activity against multiple human cancer cell lines","volume":"215","author":"Xu","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"B106","doi-asserted-by":"publisher","first-page":"2338932","DOI":"10.1080\/0886022X.2024.2338932","article-title":"USP25 attenuates anti-GBM nephritis in mice by negative feedback regulation of Th17 cell differentiation","volume":"46","author":"Xu","year":"2024","journal-title":"Ren. Fail"},{"key":"B107","doi-asserted-by":"publisher","first-page":"475","DOI":"10.7150\/ijbs.99345","article-title":"USP25 stabilizes STAT6 to promote IL-4-induced macrophage M2 polarization and fibrosis","volume":"21","author":"Xu","year":"2025","journal-title":"Int. J. Biol. Sci."},{"key":"B108","doi-asserted-by":"publisher","first-page":"e2516471123","DOI":"10.1073\/pnas.2516471123","article-title":"USP25 inhibition ameliorates Parkinson's disease by restoring mitophagy","volume":"123","author":"Xu","year":"2026","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B109","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.bbrc.2023.05.111","article-title":"Upregulation of USP25 promotes progression of human diffuse large B-cell lymphoma through blocking the ubiquitinated degradation of MDM2","volume":"676","author":"Yang","year":"","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B110","doi-asserted-by":"publisher","first-page":"109279","DOI":"10.1016\/j.clim.2023.109279","article-title":"USP25-PKM2-glycolysis axis contributes to ischemia reperfusion-induced acute kidney injury by promoting M1-like macrophage polarization and proinflammatory response","volume":"251","author":"Yang","year":"","journal-title":"Clin. Immunol."},{"key":"B111","doi-asserted-by":"publisher","first-page":"1768","DOI":"10.1016\/j.devcel.2025.01.015","article-title":"KRAS4B oncogenic mutants promote non-small cell lung cancer progression via the interaction of deubiquitinase USP25 with RNF31","volume":"60","author":"Yang","year":"2025","journal-title":"Dev. Cell."},{"key":"B112","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1161\/CIRCRESAHA.122.321849","article-title":"USP25 ameliorates pathological cardiac hypertrophy by stabilizing SERCA2a in cardiomyocytes","volume":"132","author":"Ye","year":"2023","journal-title":"Circ. Res."},{"key":"B113","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1016\/j.jacbts.2024.06.001","article-title":"Deubiquitinase USP25 alleviates obesity-induced cardiac remodeling and dysfunction by downregulating TAK1 and reducing TAK1-Mediated inflammation","volume":"9","author":"Ye","year":"2024","journal-title":"JACC Basic Transl. Sci."},{"key":"B114","doi-asserted-by":"publisher","first-page":"e70243","DOI":"10.1002\/ctm2.70243","article-title":"Ubiquitin-specific protease 25 improves myocardial ischemia-reperfusion injury by deubiquitinating NLRP3 and negatively regulating NLRP3 inflammasome activity in cardiomyocytes","volume":"15","author":"Ye","year":"","journal-title":"Clin. Transl. Med."},{"key":"B115","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1038\/s41419-025-07713-x","article-title":"USP25-driven KIFC1 regulates MYCBP expression and promotes the progression of cervical cancer","volume":"16","author":"Ye","year":"","journal-title":"Cell. Death Dis."},{"key":"B116","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s40659-019-0213-z","article-title":"Identification of the targets of hematoporphyrin derivative in lung adenocarcinoma using integrated network analysis","volume":"52","author":"Yin","year":"2019","journal-title":"Biol. Res."},{"key":"B117","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1016\/j.jacbts.2024.08.001","article-title":"Targeting USP25 in the heart: a promising therapeutic strategy for obesity-associated heart disease?","volume":"9","author":"Zhang","year":"2024","journal-title":"JACC Basic Transl. Sci."},{"key":"B118","doi-asserted-by":"publisher","first-page":"155649","DOI":"10.1016\/j.phymed.2024.155649","article-title":"The pathological mechanisms and potential therapeutic drugs for myocardial ischemia reperfusion injury","volume":"129","author":"Zhang","year":"","journal-title":"Phytomedicine"},{"key":"B119","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/s41392-024-01800-9","article-title":"Protein neddylation and its role in health and diseases","volume":"9","author":"Zhang","year":"","journal-title":"Signal Transduct. Target Ther."},{"key":"B120","doi-asserted-by":"publisher","first-page":"166713","DOI":"10.1016\/j.bbadis.2023.166713","article-title":"USP25 inhibits renal fibrosis by regulating TGFbeta-SMAD signaling pathway in Ang II-induced hypertensive mice","volume":"1869","author":"Zhao","year":"2023","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B121","doi-asserted-by":"publisher","first-page":"217270","DOI":"10.1016\/j.canlet.2024.217270","article-title":"The splicing factor QKI inhibits metastasis by modulating alternative splicing of E-Syt2 in papillary thyroid carcinoma","volume":"604","author":"Zhao","year":"2024","journal-title":"Cancer Lett."},{"key":"B122","doi-asserted-by":"publisher","first-page":"eabe1340","DOI":"10.1126\/sciadv.abe1340","article-title":"Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer's brains is mediated by USP25","volume":"7","author":"Zheng","year":"2021","journal-title":"Sci. Adv."},{"key":"B123","doi-asserted-by":"publisher","first-page":"e152170","DOI":"10.1172\/JCI152170","article-title":"USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Abeta generation","volume":"132","author":"Zheng","year":"2022","journal-title":"J. Clin. Invest."},{"key":"B124","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1038\/ni.2427","article-title":"Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25","volume":"13","author":"Zhong","year":"2012","journal-title":"Nat. Immunol."},{"key":"B125","doi-asserted-by":"publisher","first-page":"ra35","DOI":"10.1126\/scisignal.2003708","article-title":"Ubiquitin-specific protease 25 regulates TLR4-dependent innate immune responses through deubiquitination of the adaptor protein TRAF3","volume":"6","author":"Zhong","year":"","journal-title":"Sci. Signal"},{"key":"B126","doi-asserted-by":"publisher","first-page":"e80976","DOI":"10.1371\/journal.pone.0080976","article-title":"Ubiquitin-specific proteases 25 negatively regulates virus-induced type I interferon signaling","volume":"8","author":"Zhong","year":"","journal-title":"PLoS One"},{"key":"B127","doi-asserted-by":"publisher","first-page":"115624","DOI":"10.1016\/j.bcp.2023.115624","article-title":"Structure and function of the highly homologous deubiquitinases ubiquitin specific peptidase 25 and 28: insights into their pathophysiological and therapeutic roles","volume":"213","author":"Zhou","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20210486","article-title":"USP52 inhibits cell proliferation by stabilizing PTEN protein in non-small cell lung cancer","volume":"41","author":"Zhu","year":"","journal-title":"Biosci. Rep."},{"key":"B129","doi-asserted-by":"publisher","first-page":"698751","DOI":"10.3389\/fcell.2021.698751","article-title":"Emerging roles of ubiquitin-specific protease 25 in diseases","volume":"9","author":"Zhu","year":"","journal-title":"Front. Cell. Dev. Biol."},{"key":"B130","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.apsb.2023.10.013","article-title":"A novel TNKS\/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer","volume":"14","author":"Zhu","year":"2024","journal-title":"Acta Pharm. Sin. B"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1802539\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T08:07:36Z","timestamp":1784794056000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1802539\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,23]]},"references-count":130,"alternative-id":["10.3389\/fcell.2026.1802539"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1802539","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,23]]},"article-number":"1802539"}}