{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T08:42:18Z","timestamp":1788856938607,"version":"build-2803163510"},"reference-count":128,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"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","award":["82304598"],"award-info":[{"award-number":["82304598"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473991"],"award-info":[{"award-number":["82473991"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Minhang District Science and Technology Commission Foundation","award":["2022MHZ013"],"award-info":[{"award-number":["2022MHZ013"]}]},{"name":"Shanghai Sailing Program","award":["22YF1439800"],"award-info":[{"award-number":["22YF1439800"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ubiquitin-specific proteases (USPs) constitute the largest and most diverse family of deubiquitinating enzymes (DUBs), playing a pivotal role in maintaining protein homeostasis through reversible post-translational modifications (PTMs). Renal fibrosis represents the final common pathway of various chronic kidney diseases (CKDs), ultimately leading to irreversible nephron loss and end-stage renal disease (ESRD). With CKD affecting over 10% of the global adult population, fibrosis imposes a substantial clinical and economic burden. Despite this, effective antifibrotic therapies remain clinically elusive. Emerging evidence highlights the critical involvement of USPs in the pathogenesis of renal fibrosis through the potentiation of pro-fibrotic signaling pathways, inflammation, oxidative stress, cell cycle arrest and cellular senescence, as well as some other pathways. This review comprehensively summarizes the current understanding of USPs in renal fibrosis, detailing their structural characteristics, molecular mechanisms, and specific regulatory roles. Furthermore, we discuss recent advances in developing small-molecule USP inhibitors, providing novel insights into targeting the ubiquitin\u2013proteasome system as a promising therapeutic strategy for combating renal fibrosis.<\/jats:p>","DOI":"10.3390\/ijms27052318","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T12:39:56Z","timestamp":1772455196000},"page":"2318","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Ubiquitin-Specific Protease Family: Master Regulators of Renal Fibrosis Pathogenesis and Therapeutic Targets"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4427-0164","authenticated-orcid":false,"given":"Yinhang","family":"Wang","sequence":"first","affiliation":[{"name":"Joint Center for Translational Medicine, Shanghai Fifth People\u2019s Hospital, Fudan University, & School of Pharmacy, East China Normal University, Shanghai 200241, China"},{"name":"Department of Neurology, Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dadui","family":"Ren","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Research, Henan Academy of Sciences, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai 200062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Joint Center for Translational Medicine, Shanghai Fifth People\u2019s Hospital, Fudan University, & School of Pharmacy, East China Normal University, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1016\/S0140-6736(25)01853-7","article-title":"Global, regional, and national burden of chronic kidney disease in adults, 1990\u20132023, and its attributable risk factors: A systematic analysis for the Global Burden of Disease Study 2023","volume":"406","author":"Mark","year":"2025","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/s41581-025-00934-5","article-title":"Advances and challenges in kidney fibrosis therapeutics","volume":"21","author":"Abbad","year":"2025","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/s41586-020-2938-9","article-title":"Fibrosis: From mechanisms to medicines","volume":"587","author":"Henderson","year":"2020","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Singhal, S., Taylor, M.C., and Baker, R.T. (2008). Deubiquitylating enzymes and disease. BMC Biochem., 9.","DOI":"10.1186\/1471-2091-9-S1-S3"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12021","DOI":"10.1016\/S0021-9258(18)99059-9","article-title":"Cloning and functional analysis of the ubiquitin-specific protease gene UBP1 of Saccharomyces cerevisiae","volume":"266","author":"Tobias","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"23364","DOI":"10.1016\/S0021-9258(18)50100-9","article-title":"Ubiquitin-specific proteases of Saccharomyces cerevisiae. Cloning of UBP2 and UBP3, and functional analysis of the UBP gene family","volume":"267","author":"Baker","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1146\/annurev-biochem-061516-044916","article-title":"Mechanisms of deubiquitinase specificity and regulation","volume":"86","author":"Mevissen","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41580-019-0099-1","article-title":"Breaking the chains: Deubiquitylating enzyme specificity begets function","volume":"20","author":"Clague","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wang, Q., Sun, Z., Xia, W., Sun, L., Du, Y., Zhang, Y., and Jia, Z. (2022). Role of USP13 in physiology and diseases. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.977122"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/S0092-8674(02)01199-6","article-title":"Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde","volume":"111","author":"Hu","year":"2002","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/nrm2731","article-title":"Breaking the chains: Structure and function of the deubiquitinases","volume":"10","author":"Komander","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1039\/B907669G","article-title":"Dissection of USP catalytic domains reveals five common insertion points","volume":"5","author":"Ye","year":"2009","journal-title":"Mol. BioSyst."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e202302533","DOI":"10.26508\/lsa.202302533","article-title":"Variety in the USP deubiquitinase catalytic mechanism","volume":"7","author":"Keijzer","year":"2024","journal-title":"Life Sci. Alliance"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1016\/j.chembiol.2011.10.017","article-title":"The differential modulation of USP activity by internal regulatory domains, interactors and eight ubiquitin chain types","volume":"18","author":"Faesen","year":"2011","journal-title":"Chem. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.dnarep.2019.02.005","article-title":"USP7: Structure, substrate specificity, and inhibition","volume":"76","author":"Pozhidaeva","year":"2019","journal-title":"DNA Repair"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.molcel.2011.06.034","article-title":"Mechanism of USP7\/HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase","volume":"44","author":"Faesen","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1038\/sj.emboj.7600832","article-title":"Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14","volume":"24","author":"Hu","year":"2005","journal-title":"EMBO J."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, F., Ning, S., Yu, B., and Wang, Y. (2022). USP14: Structure, function, and target inhibition. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.801328"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dash, R., Tran, N.-N., Lee, S.B., and Lee, B.-H. (2024). Structural Dynamics Analysis of USP14 Activation by AKT-Mediated Phosphorylation. Cells, 13.","DOI":"10.3390\/cells13110955"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1002\/pro.3675","article-title":"Structural and functional studies of USP20 ZnF-UBP domain by NMR","volume":"28","author":"Yang","year":"2019","journal-title":"Protein Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1002\/pro.2692","article-title":"Structural insights into interactions between ubiquitin specific protease 5 and its polyubiquitin substrates by mass spectrometry and ion mobility spectrometry","volume":"24","author":"Scott","year":"2015","journal-title":"Protein Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.1021\/bi500116x","article-title":"Structure and catalytic regulatory function of ubiquitin specific protease 11 N-terminal and ubiquitin-like domains","volume":"53","author":"Harper","year":"2014","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2510496122","DOI":"10.1073\/pnas.2510496122","article-title":"Small-molecule allosteric activator of ubiquitin-specific protease 7 (USP7)","volume":"122","author":"Sharafi","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"17362","DOI":"10.1074\/jbc.RA118.003857","article-title":"The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel","volume":"293","author":"Ward","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1016\/j.str.2025.06.005","article-title":"Structures of USP7 in active and inactive states bound to DNMT1 revealed by cryo-EM","volume":"33","author":"Nakamura","year":"2025","journal-title":"Structure"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhang, S., Zou, S., Yin, D., Finley, D., Wu, Z., and Mao, Y. (2021). Mechanistic insights into dynamic mutual regulation of USP14 and proteasome. bioRxiv.","DOI":"10.1101\/2021.09.15.460436"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"107727","DOI":"10.1016\/j.jbc.2024.107727","article-title":"Autoinhibition of ubiquitin-specific protease 8: Insights into domain interactions and mechanisms of regulation","volume":"300","author":"Caba","year":"2024","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1002\/1873-3468.13017","article-title":"Biophysical and structural insight into the USP8\/14-3-3 interaction","volume":"592","author":"Centorrino","year":"2018","journal-title":"FEBS Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15557","DOI":"10.1021\/acs.jmedchem.4c01184","article-title":"Structural and biochemical insights into the mechanism of action of the clinical USP1 inhibitor, KSQ-4279","volume":"67","author":"Rennie","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.molcel.2016.05.031","article-title":"Allosteric activation of ubiquitin-specific proteases by \u03b2-propeller proteins UAF1 and WDR20","volume":"63","author":"Li","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/s41421-019-0102-1","article-title":"Structural insights into the activation of USP46 by WDR48 and WDR20","volume":"5","author":"Zhu","year":"2019","journal-title":"Cell Discov."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5687","DOI":"10.1038\/s44319-024-00300-9","article-title":"The USP12\/46 deubiquitinases protect integrins from ESCRT-mediated lysosomal degradation","volume":"25","author":"Yu","year":"2024","journal-title":"EMBO Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1126\/science.aac5681","article-title":"Structural basis for histone H2B deubiquitination by the SAGA DUB module","volume":"351","author":"Morgan","year":"2016","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3734","DOI":"10.1128\/MCB.05231-11","article-title":"The tightly controlled deubiquitination activity of the human SAGA complex differentially modifies distinct gene regulatory elements","volume":"31","author":"Lang","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.cell.2010.04.026","article-title":"Structural basis for assembly and activation of the heterotetrameric SAGA histone H2B deubiquitinase module","volume":"141","author":"Zimmerman","year":"2010","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.chembiol.2021.12.004","article-title":"Potent macrocycle inhibitors of the human SAGA deubiquitinating module","volume":"29","author":"Morgan","year":"2022","journal-title":"Cell Chem. Biol."},{"key":"ref_37","first-page":"151","article-title":"A Novel Regulatory Mechanism to Regulate the Deubiquitinating Activity of USP25 by Oligomerization","volume":"1","author":"Li","year":"2020","journal-title":"J. Cell. Signal."},{"key":"ref_38","doi-asserted-by":"crossref","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":"ref_39","first-page":"759","article-title":"An element of the transforming growth factor-beta 1 5\u2032-untranslated region represses translation and specifically binds a cytosolic factor","volume":"7","author":"Romeo","year":"1993","journal-title":"Mol. Endocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3493","DOI":"10.1113\/JP274492","article-title":"Transforming growth factor-\u03b2 signalling in renal fibrosis: From SMADs to non-coding RNAs","volume":"596","author":"Tang","year":"2018","journal-title":"J. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Meng, X.-M., Tang, P.M.-K., Li, J., and Lan, H.Y. (2015). TGF-\u03b2\/SMAD signaling in renal fibrosis. Front. Physiol., 6.","DOI":"10.3389\/fphys.2015.00082"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"F596","DOI":"10.1152\/ajprenal.00365.2015","article-title":"TGF-\u03b2 signaling in the kidney: Profibrotic and protective effects","volume":"310","author":"Sureshbabu","year":"2016","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1007\/s00018-018-2949-y","article-title":"TGF-\u03b2 signaling pathway mediated by deubiquitinating enzymes","volume":"76","author":"Kim","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.krcp.2011.12.001","article-title":"SMADs as therapeutic targets for chronic kidney disease","volume":"31","author":"Lan","year":"2012","journal-title":"Kidney Res. Clin. Pract."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1681\/ASN.2009121244","article-title":"SMAD2 protects against TGF-\u03b2\/SMAD3-mediated renal fibrosis","volume":"21","author":"Meng","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/37284","article-title":"TGF-\u03b2 signalling from cell membrane to nucleus through SMAD proteins","volume":"390","author":"Heldin","year":"1997","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/cr.2008.325","article-title":"Nucleocytoplasmic shuttling of SMAD proteins","volume":"19","author":"Hill","year":"2009","journal-title":"Cell Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1074\/jbc.M115.694281","article-title":"SMAD7 protein interacts with receptor-regulated SMADs (R-SMADs) to inhibit transforming growth factor-\u03b2 (TGF-\u03b2)\/SMAD signaling","volume":"291","author":"Yan","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/39369","article-title":"Identification of SMAD7, a TGF\u03b2-inducible antagonist of TGF-\u03b2 signalling","volume":"389","author":"Nakao","year":"1997","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/abbs\/gmp018","article-title":"Regulation of TGF-\u03b2 signaling by SMAD7","volume":"41","author":"Yan","year":"2009","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/ncb2522","article-title":"USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-\u03b2 type I receptor","volume":"14","author":"Zhang","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1007\/s11596-022-2632-2","article-title":"Inhibition of Ubiquitin-specific Protease 4 Attenuates Epithelial\u2014Mesenchymal Transition of Renal Tubular Epithelial Cells via Transforming Growth Factor Beta Receptor Type I","volume":"42","author":"Pu","year":"2022","journal-title":"Curr. Med. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"120063","DOI":"10.1098\/rsob.120063","article-title":"USP11 augments TGF\u03b2 signalling by deubiquitylating ALK5","volume":"2","author":"Herhaus","year":"2012","journal-title":"Open Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e2474","DOI":"10.1038\/cddis.2016.371","article-title":"De-ubiquitinating enzyme, USP11, promotes transforming growth factor \u03b2-1 signaling through stabilization of transforming growth factor \u03b2 receptor II","volume":"7","author":"Jacko","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1038\/s42003-025-09286-z","article-title":"Lactate orchestrates the TGF\u03b2 pathway and ferroptosis nexus in organ fibrosis via USP2 lactylation","volume":"8","author":"Xiang","year":"2025","journal-title":"Commun. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Das, T., Song, E.J., and Kim, E.E. (2021). The multifaceted roles of USP15 in signal transduction. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094728"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nm.2619","article-title":"USP15 stabilizes TGF-\u03b2 receptor I and promotes oncogenesis through the activation of TGF-\u03b2 signaling in glioblastoma","volume":"18","author":"Eichhorn","year":"2012","journal-title":"Nat. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e108791","DOI":"10.15252\/embj.2021108791","article-title":"USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-\u03b2 receptor T\u03b2RII","volume":"41","author":"Xie","year":"2022","journal-title":"EMBO J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"167660","DOI":"10.1016\/j.bbadis.2025.167660","article-title":"Ubiquitin-specific peptidase 10 promotes renal interstitial fibrosis progression through deubiquitinating and stabilizing P53 protein","volume":"1871","author":"Liu","year":"2025","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cellsig.2017.11.005","article-title":"TGF-\u03b21\/p53 signaling in renal fibrogenesis","volume":"43","author":"Higgins","year":"2018","journal-title":"Cell. Signal."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s00441-011-1181-y","article-title":"TGF-\u03b21\u2192 SMAD\/p53\/USF2\u2192 PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis","volume":"347","author":"Samarakoon","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1186\/s10020-025-01296-1","article-title":"Ubiquitin-specific protease 38 modulates atrial fibrillation susceptibility in chronic kidney disease via STRAP stabilization and activation of TGF-\u03b2\/SMAD signaling","volume":"31","author":"Meng","year":"2025","journal-title":"Mol. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"166713","DOI":"10.1016\/j.bbadis.2023.166713","article-title":"USP25 inhibits renal fibrosis by regulating TGF\u03b2-SMAD signaling pathway in Ang II-induced hypertensive mice","volume":"1869","author":"Zhao","year":"2023","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.24976\/Discov.Med.202436187.148","article-title":"USP7 Promotes TGF-\u03b21 Signaling by De-Ubiquitinating SMAD2\/SMAD3 in Pulmonary Fibrosis","volume":"36","author":"Tang","year":"2024","journal-title":"Discov. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5793","DOI":"10.7150\/thno.97767","article-title":"Knocking out USP7 attenuates cardiac fibrosis and endothelial-to-mesenchymal transition by destabilizing SMAD3 in mice with heart failure with preserved ejection fraction","volume":"14","author":"Yuan","year":"2024","journal-title":"Theranostics"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1038\/ncb2346","article-title":"USP15 is a deubiquitylating enzyme for receptor-activated SMADs","volume":"13","author":"Inui","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.cell.2008.10.051","article-title":"FAM\/USP9x, a deubiquitinating enzyme essential for TGF\u03b2 signaling, controls SMAD4 monoubiquitination","volume":"136","author":"Dupont","year":"2009","journal-title":"Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1002\/1878-0261.12596","article-title":"Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing SMAD4 protein","volume":"14","author":"Yuan","year":"2020","journal-title":"Mol. Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"797","DOI":"10.15252\/embr.201643270","article-title":"USP 26 regulates TGF-\u03b2 signaling by deubiquitinating and stabilizing SMAD 7","volume":"18","author":"Iyengar","year":"2017","journal-title":"EMBO Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e12424","DOI":"10.1002\/advs.202512424","article-title":"Activating the Osteoblastic USP26 Pathway Alleviates Multi-Organ Fibrosis by Decreasing Insulin Resistance","volume":"13","author":"Tang","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2597","DOI":"10.1038\/s41388-022-02275-0","article-title":"Loss of deubiquitylase USP2 triggers development of glioblastoma via TGF-\u03b2 signaling","volume":"41","author":"Tu","year":"2022","journal-title":"Oncogene"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/s41581-020-00343-w","article-title":"WNT\u2013\u03b2-catenin signalling\u2014A versatile player in kidney injury and repair","volume":"17","author":"Schunk","year":"2021","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Li, S.-S., Sun, Q., Hua, M.-R., Suo, P., Chen, J.-R., Yu, X.-Y., and Zhao, Y.-Y. (2021). Targeting the Wnt\/\u03b2-catenin signaling pathway as a potential therapeutic strategy in renal tubulointerstitial fibrosis. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.719880"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/kisup.2014.16","article-title":"Wnt\/\u03b2-catenin signaling and kidney fibrosis","volume":"4","author":"Tan","year":"2014","journal-title":"Kidney Int. Suppl."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Zhu, S., Hou, S., Lu, Y., Sheng, W., Cui, Z., Dong, T., Feng, H., and Wan, Q. (2021). USP36-mediated deubiquitination of DOCK4 contributes to the diabetic renal tubular epithelial cell injury via wnt\/\u03b2-catenin signaling pathway. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.638477"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4184","DOI":"10.1038\/s41467-019-12143-3","article-title":"USP7 inhibits Wnt\/\u03b2-catenin signaling through promoting stabilization of Axin","volume":"10","author":"Ji","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_77","first-page":"1823","article-title":"Ubiquitin-specific peptidase 2a (USP2a) deubiquitinates and stabilizes \u03b2-catenin","volume":"8","author":"Kim","year":"2018","journal-title":"Am. J. Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1128\/MCB.01094-10","article-title":"The Ubiquitin-Specific Protease USP34 Regulates Axin Stability and Wnt\/\u03b2-Catenin Signaling","volume":"31","author":"Lui","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1016\/j.molonc.2015.06.006","article-title":"Ubiquitin specific protease 4 positively regulates the WNT\/\u03b2-catenin signaling in colorectal cancer","volume":"9","author":"Yun","year":"2015","journal-title":"Mol. Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1111\/j.1582-4934.2008.00682.x","article-title":"The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway","volume":"13","author":"Zhao","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"E2945","DOI":"10.1073\/pnas.1605691113","article-title":"USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds","volume":"113","author":"Madan","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e64","DOI":"10.1038\/oncsis.2013.28","article-title":"Deubiquitination of Dishevelled by Usp14 is required for Wnt signaling","volume":"2","author":"Jung","year":"2013","journal-title":"Oncogenesis"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"111784","DOI":"10.1016\/j.cbi.2025.111784","article-title":"Oxidative stress and inflammation in renal fibrosis: Novel molecular mechanisms and therapeutic targets","volume":"421","author":"Liu","year":"2025","journal-title":"Chem.-Biol. Interact."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Ren, N., Wang, W.-F., Zou, L., Zhao, Y.-L., Miao, H., and Zhao, Y.-Y. (2024). The nuclear factor kappa B signaling pathway is a master regulator of renal fibrosis. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1335094"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s13578-015-0056-4","article-title":"NF-\u03baB in inflammation and renal diseases","volume":"5","author":"Zhang","year":"2015","journal-title":"Cell Biosci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3982906","DOI":"10.1155\/2017\/3982906","article-title":"CYLD Deubiquitinase Negatively Regulates High Glucose-Induced NF-\u03baB Inflammatory Signaling in Mesangial Cells","volume":"2017","author":"Li","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_87","doi-asserted-by":"crossref","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":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2301641","DOI":"10.1002\/advs.202301641","article-title":"USP25 inhibits neuroinflammatory responses after cerebral ischemic stroke by deubiquitinating TAB2","volume":"10","author":"Li","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/s41401-023-01192-6","article-title":"OTUD1 promotes hypertensive kidney fibrosis and injury by deubiquitinating CDK9 in renal epithelial cells","volume":"45","author":"Wang","year":"2024","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"C400","DOI":"10.1152\/ajpcell.00394.2023","article-title":"OTUD6A in tubular epithelial cells mediates angiotensin II-induced kidney injury by targeting STAT3","volume":"326","author":"Sun","year":"2024","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"eadx3827","DOI":"10.1126\/sciadv.adx3827","article-title":"USP13 stabilizes NLRP3 to facilitate inflammasome activation by preventing TRIM31-mediated NLRP3 ubiquitination and degradation","volume":"11","author":"Li","year":"2025","journal-title":"Sci. Adv."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"11754","DOI":"10.1074\/jbc.RA120.014113","article-title":"The deubiquitinase USP7 uses a distinct ubiquitin-like domain to deubiquitinate NF-\u0138B subunits","volume":"295","author":"Mitxitorena","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41420-025-02481-1","article-title":"USP7 promotes endothelial activation to aggravate sepsis-induced acute lung injury through PDK1\/AKT\/NF-\u03baB signaling pathway","volume":"11","author":"Liu","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1007\/978-981-13-8871-2_29","article-title":"Oxidative stress and renal fibrosis: Mechanisms and therapies","volume":"1165","author":"Su","year":"2019","journal-title":"Ren. Fibros. Mech. Ther."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/WOX.0b013e3182439613","article-title":"Oxidative stress and antioxidant defense","volume":"5","author":"Birben","year":"2012","journal-title":"World Allergy Organ. J."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Kuang, F., Liu, J., Tang, D., and Kang, R. (2020). Oxidative damage and antioxidant defense in ferroptosis. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.586578"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41388-023-02907-z","article-title":"ROS production by mitochondria: Function or dysfunction?","volume":"43","author":"Palma","year":"2024","journal-title":"Oncogene"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"102280","DOI":"10.1016\/j.trim.2025.102280","article-title":"ELAVL1-stabilized USP22 promotes diabetic nephropathy progression via mediating podocyte injury and death by triggering ACSL4 deubiquitination","volume":"93","author":"Wang","year":"2025","journal-title":"Transpl. Immunol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1165\/rcmb.2022-0002OC","article-title":"USP13 deficiency impairs autophagy and facilitates age-related lung fibrosis","volume":"68","author":"Liu","year":"2023","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1080\/15548627.2022.2072054","article-title":"Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis","volume":"19","author":"Livingston","year":"2023","journal-title":"Autophagy"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"112100","DOI":"10.1016\/j.yexcr.2020.112100","article-title":"USP9X prevents AGEs-induced upregulation of FN and TGF-\u03b21 through activating Nrf2-ARE pathway in rat glomerular mesangial cells","volume":"393","author":"Huang","year":"2020","journal-title":"Exp. Cell Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1186\/s13046-021-02026-1","article-title":"Kidney cancer biomarkers and targets for therapeutics: Survivin (BIRC5), XIAP, MCL-1, HIF1\u03b1, HIF2\u03b1, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma","volume":"40","author":"Li","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2411320","DOI":"10.1002\/advs.202411320","article-title":"Redox-Induced Stabilization of AMBRA1 by USP7 Promotes Intestinal Oxidative Stress and Colitis Through Antagonizing DUB3-Mediated NRF2 Deubiquitination","volume":"12","author":"Xu","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Hao, W., Li, M., Cai, Q., Wu, S., Li, X., He, Q., and Hu, Y. (2022). Roles of NRF2 in fibrotic diseases: From mechanisms to therapeutic approaches. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.889792"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.7150\/ijms.107284","article-title":"The roles of the ubiquitin-proteasome system in renal disease","volume":"22","author":"Lu","year":"2025","journal-title":"Int. J. Med. Sci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/nm.2144","article-title":"Epithelial cell cycle arrest in G2\/M mediates kidney fibrosis after injury","volume":"16","author":"Yang","year":"2010","journal-title":"Nat. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1093\/jmcb\/mjy042","article-title":"p53 upregulated by HIF-1 \u03b1 promotes hypoxia-induced G2\/M arrest and renal fibrosis in vitro and in vivo","volume":"11","author":"Liu","year":"2019","journal-title":"J. Mol. Cell Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.kint.2022.11.027","article-title":"Ubiquitin-specific protease 11 promotes partial epithelial-to-mesenchymal transition by deubiquitinating the epidermal growth factor receptor during kidney fibrosis","volume":"103","author":"Shi","year":"2023","journal-title":"Kidney Int."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/s41401-022-00977-5","article-title":"Deubiquitinating enzyme USP11 promotes renal tubular cell senescence and fibrosis via inhibiting the ubiquitin degradation of TGF-\u03b2 receptor II","volume":"44","author":"Ni","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"7527","DOI":"10.18632\/aging.204301","article-title":"Ubiquitin-like protein FAT10 promotes renal fibrosis by stabilizing USP7 to prolong CHK1-mediated G2\/M arrest in renal tubular epithelial cells","volume":"14","author":"Shao","year":"2022","journal-title":"Aging"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"e13117","DOI":"10.1111\/acel.13117","article-title":"Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity","volume":"19","author":"He","year":"2020","journal-title":"Aging Cell"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.trsl.2024.04.002","article-title":"Inhibition of Usp14 ameliorates renal ischemia-reperfusion injury by reducing Tfap2a stabilization and facilitating mitophagy","volume":"270","author":"Li","year":"2024","journal-title":"Transl. Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.mito.2022.08.004","article-title":"Receptor-mediated mitophagy: An emerging therapeutic target in acute kidney injury","volume":"66","author":"Dagar","year":"2022","journal-title":"Mitochondrion"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1038\/s42255-023-00930-8","article-title":"Mitophagy in human health, ageing and disease","volume":"5","author":"Picca","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1681\/ASN.20233411S127a","article-title":"MTX652, a Novel Selective USP30 Inhibitor for the Treatment of AKI: Phase 1 Results in Healthy Subjects and Model-Driven Human Efficacious Dose Projections: TH-OR93","volume":"34","author":"Aceves","year":"2023","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41401-024-01363-z","article-title":"USP11 promotes renal tubular cell pyroptosis and fibrosis in UUO mice via inhibiting KLF4 ubiquitin degradation","volume":"46","author":"Wang","year":"2025","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"175671","DOI":"10.1016\/j.ejphar.2023.175671","article-title":"USP22 aggravated diabetic renal tubulointerstitial fibrosis progression through deubiquitinating and stabilizing Snail1","volume":"947","author":"Zhao","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Bailly, C., and Vergoten, G. (2022). Binding of Vialinin A and p-Terphenyl Derivatives to Ubiquitin-Specific Protease 4 (USP4): A Molecular Docking Study. Molecules, 27.","DOI":"10.3390\/molecules27185909"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"4328","DOI":"10.1016\/j.bmcl.2013.05.093","article-title":"Vialinin A is a ubiquitin-specific peptidase inhibitor","volume":"23","author":"Okada","year":"2013","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"151095","DOI":"10.1016\/j.bbrc.2024.151095","article-title":"Deubiquitinase inhibitor bAP-15 suppresses renal epithelial to mesenchymal transition via inhibition of p300 stability","volume":"741","author":"Kim","year":"2024","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"11990","DOI":"10.1039\/D4FO03564J","article-title":"Quercetin prevents the USP22-Snail1 signaling pathway to ameliorate diabetic tubulointerstitial fibrosis","volume":"15","author":"Zhao","year":"2024","journal-title":"Food Funct."},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Li, X., Xu, R., Zhang, D., Cai, J., Zhou, H., Song, T., Wang, X., Kong, Q., Li, L., and Liu, Z. (2025). Baicalin: A potential therapeutic agent for acute kidney injury and renal fibrosis. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1511083"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"114917","DOI":"10.1016\/j.celrep.2024.114917","article-title":"USP7 deubiquitinates KRAS and promotes non-small cell lung cancer","volume":"43","author":"Huang","year":"2024","journal-title":"Cell Rep."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Soji, K., Doi, S., Nakashima, A., Sasaki, K., Doi, T., and Masaki, T. (2018). Deubiquitinase inhibitor PR-619 reduces SMAD4 expression and suppresses renal fibrosis in mice with unilateral ureteral obstruction. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202409"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1007\/s13238-017-0486-3","article-title":"The role of ubiquitination and deubiquitination in the regulation of cell junctions","volume":"9","author":"Cai","year":"2018","journal-title":"Protein Cell"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Delrue, C., and Speeckaert, M.M. (2025). Renal Implications of Dysregulated Protein Homeostasis: Insights into Ubiquitin\u2013Proteasome and Autophagy Systems. Biomolecules, 15.","DOI":"10.3390\/biom15030349"},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Reis-Mendes, A., Dores-Sousa, J.L., Padr\u00e3o, A.I., Duarte-Ara\u00fajo, M., Duarte, J.A., Seabra, V., Gon\u00e7alves-Monteiro, S., Remi\u00e3o, F., Carvalho, F., and Sousa, E. (2021). Inflammation as a possible trigger for mitoxantrone-induced cardiotoxicity: An in vivo study in adult and infant mice. Pharmaceuticals, 14.","DOI":"10.3390\/ph14060510"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"582804","DOI":"10.2147\/IJN.S582804","article-title":"Engineering Kidney-Targeted Drug Delivery Systems: Principles, Materials, and Emerging Strategies","volume":"21","author":"Wang","year":"2026","journal-title":"Int. J. Nanomed."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2318\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T12:46:07Z","timestamp":1772455567000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,1]]},"references-count":128,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27052318"],"URL":"https:\/\/doi.org\/10.3390\/ijms27052318","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,1]]}}}