{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T19:05:38Z","timestamp":1788462338341,"version":"build-2803163510"},"reference-count":39,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,30]],"date-time":"2023-07-30T00:00:00Z","timestamp":1690675200000},"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":["82000919"],"award-info":[{"award-number":["82000919"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Scar formation resulting from overly active wound healing is a critical factor in the success rate of glaucoma filtration surgery (GFS). IL-6 and TGF-\u03b2 have been implicated in the pathogenesis of fibrogenesis. In addition, the signal transducer and activator of transcription 3 (STAT3) can be activated by numerous cytokines and growth factors, including IL-6 and TGF-\u03b21. Thus, STAT3 activation may integrate common profibrotic pathways to promote fibrosis. In this study, an increase in p-STAT3 was observed in activated HTFs. Inhibiting STAT3 in cultured HTFs by pharmacological inactivation reversed the fibrotic responses, such as fibroblast migration, the differentiation of resting fibroblasts into myofibroblasts and the deposition of ECM, mediated by IL-6 and TGF-\u03b21. Moreover, the expression of suppressor of cytokine signaling 3 (SOCS3) was decreased in HTFs cultured with IL-6 and TGF-\u03b21, and SOCS3 overexpression rescued ECM deposition, \u03b1-SMA expression and migration in IL-6- and TGF-\u03b21-stimulated HTFs by inactivating STAT3. Finally, S3I-201 treatment inhibited profibrotic gene expression and subconjunctival fibrosis in a rat model of GFS. In conclusion, our data suggests that STAT3 plays a central role in fibrosis induced by different profibrotic pathways and that STAT3 is a potential target for antifibrotic therapies following GFS.<\/jats:p>","DOI":"10.3390\/ijms241512210","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T01:28:46Z","timestamp":1690766926000},"page":"12210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Role of STAT3 Signaling Pathway Activation in Subconjunctival Scar Formation after Glaucoma Filtration Surgery"],"prefix":"10.3390","volume":"24","author":[{"given":"Yanxia","family":"Li","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, The Second Hospital of Jilin University, Jilin University, Changchun 130041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Hospital of Jilin University, Jilin University, Changchun 130041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Hospital of Jilin University, Jilin University, Changchun 130041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenchen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Hospital of Jilin University, Jilin University, Changchun 130041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Hospital of Jilin University, Jilin University, Changchun 130041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2327-3733","authenticated-orcid":false,"given":"Yajuan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Second Hospital of Jilin University, Jilin University, Changchun 130041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis","volume":"121","author":"Wong","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20406223221140392","DOI":"10.1177\/20406223221140392","article-title":"Current situation and progress of drugs for reducing intraocular pressure","volume":"13","author":"Liu","year":"2022","journal-title":"Ther. Adv. Chronic Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/vop.12858","article-title":"Looking into the future: Gene and cell therapies for glaucoma","volume":"24","author":"Koehl","year":"2021","journal-title":"Veter Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ophtha.2017.08.028","article-title":"Modulation of Fibroblasts in Conjunctival Wound Healing","volume":"125","author":"Zada","year":"2018","journal-title":"Ophthalmology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.survophthal.2020.05.005","article-title":"Learning from the past: Mitomycin C use in trabeculectomy and its application in bleb-forming minimally invasive glaucoma surgery","volume":"66","author":"Bell","year":"2021","journal-title":"Surv. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1001\/archopht.120.3.297","article-title":"Incidence of Late-Onset Bleb-Related Complications following Trabeculectomy with Mitomycin","volume":"120","author":"DeBry","year":"2002","journal-title":"Arch. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/s00417-002-0621-5","article-title":"Five-year results of trabeculectomy with mitomycin C","volume":"241","author":"Beckers","year":"2003","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1136\/bjo.2005.077800","article-title":"Mitomycin C augmented glaucoma surgery: Evolution of filtering bleb avascularity, transconjunctival oozing, and leaks","volume":"90","author":"Anand","year":"2006","journal-title":"Br. J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.immuni.2013.10.022","article-title":"Interleukin-6 Signaling Drives Fibrosis in Unresolved Inflammation","volume":"40","author":"Fielding","year":"2014","journal-title":"Immunity"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.cytogfr.2012.04.003","article-title":"Interleukin-6, its role in fibrosing conditions","volume":"23","author":"Ciechomska","year":"2012","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1161\/HYPERTENSIONAHA.118.12267","article-title":"HIMF (Hypoxia-Induced Mitogenic Factor)-IL (Interleukin)-6 Signaling Mediates Cardiomyocyte-Fibroblast Crosstalk to Promote Cardiac Hypertrophy and Fibrosis","volume":"73","author":"Kumar","year":"2019","journal-title":"Hypertension"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1042\/CS20110340","article-title":"IL-6\/IL-6 receptor system and its role in physiological and pathological conditions","volume":"122","author":"Mihara","year":"2012","journal-title":"Clin. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/ni.3153","article-title":"IL-6 as a keystone cytokine in health and disease","volume":"16","author":"Hunter","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/S1074-7613(04)00003-2","article-title":"IL-6 trans-signaling: The heat is on","volume":"20","author":"Neurath","year":"2004","journal-title":"Immunity"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj20030407","article-title":"Principles of interleukin (IL)-6-type cytokine signalling and its regulation","volume":"374","author":"Heinrich","year":"2003","journal-title":"Biochem. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/nrc2734","article-title":"STATs in cancer inflammation and immunity: A leading role for STAT3","volume":"9","author":"Yu","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1096\/fj.15-273953","article-title":"STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation","volume":"30","author":"Pedroza","year":"2016","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1038\/s41467-017-01236-6","article-title":"Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis","volume":"8","author":"Chakraborty","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/ki.2010.154","article-title":"A novel STAT3 inhibitor, S3I-201, attenuates renal interstitial fibroblast activation and interstitial fibrosis in obstructive nephropathy","volume":"78","author":"Pang","year":"2010","journal-title":"Kidney Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s11658-017-0034-4","article-title":"A simple and effective protocol for fast isolation of human Tenon\u2019s fibroblasts from a single trabeculectomy biopsy\u2014A comparison of cell behaviour in different culture media","volume":"22","author":"Przekora","year":"2017","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.exer.2012.04.015","article-title":"Different fibroblast subpopulations of the eye: A therapeutic target to prevent postoperative fibrosis in glaucoma therapy","volume":"100","author":"Stahnke","year":"2012","journal-title":"Exp. Eye Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.7150\/ijbs.67974","article-title":"LncRNA-COX2 inhibits Fibroblast Activation and Epidural Fibrosis by Targeting EGR1","volume":"18","author":"Yang","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12943-021-01377-9","article-title":"EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK\/STAT signaling","volume":"20","author":"Liu","year":"2021","journal-title":"Mol. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1097\/ICU.0000000000000729","article-title":"History, presence, and future of mitomycin C in glaucoma filtration surgery","volume":"32","author":"Wolters","year":"2020","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.ajo.2011.10.026","article-title":"Treatment Outcomes in the Tube Versus Trabeculectomy (TVT) Study after Five Years of Follow-up","volume":"153","author":"Gedde","year":"2012","journal-title":"Am. J. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/S0161-6420(85)33948-9","article-title":"Complications of surgery in glaucoma. Early and late bacterial endophthalmitis following glaucoma filtering surgery","volume":"92","author":"Katz","year":"1985","journal-title":"Ophthalmology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.exer.2015.03.021","article-title":"Conjunctival fibrosis following filtering glaucoma surgery","volume":"142","author":"Schlunck","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12886-015-0134-8","article-title":"Pathobiology of wound healing after glaucoma filtration surgery","volume":"15","author":"Yamanaka","year":"2015","journal-title":"BMC Ophthalmol."},{"key":"ref_29","first-page":"R1840","article-title":"Interleukin-6 activity in wounds","volume":"266","author":"Mateo","year":"1994","journal-title":"Am. J. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/nature07039","article-title":"Wound repair and regeneration","volume":"453","author":"Gurtner","year":"2008","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/S1357-2725(98)00067-3","article-title":"SOCS: Suppressors of cytokine signalling","volume":"30","author":"Starr","year":"1998","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7391","DOI":"10.1073\/pnas.0609757104","article-title":"Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity","volume":"104","author":"Siddiquee","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/379645a0","article-title":"Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor","volume":"379","author":"Meydan","year":"1996","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Shawky, A.M., Almalki, F.A., Abdalla, A.N., Abdelazeem, A.H., and Gouda, A.M. (2022). A Comprehensive Overview of Globally Approved JAK Inhibitors. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14051001"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1084\/jem.20080003","article-title":"Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-{beta} and STAT3 activation","volume":"206","author":"Hosui","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/S0002-9440(10)61210-2","article-title":"Susceptibility of Signal Transducer and Activator of Transcription-1-Deficient Mice to Pulmonary Fibrogenesis","volume":"167","author":"Walters","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"108708","DOI":"10.1016\/j.exer.2021.108708","article-title":"Potential roles of the IL-6 family in conjunctival fibrosis","volume":"210","author":"Ogawa","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"662","DOI":"10.4103\/ijo.IJO_2037_21","article-title":"A modified model of glaucoma filtering surgery in Sprague-Dawley rats","volume":"70","author":"Pandav","year":"2022","journal-title":"Indian J. Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1097\/01.ijg.0000131482.86547.5a","article-title":"A New Model of Glaucoma Filtering Surgery in the Rat","volume":"13","author":"Sherwood","year":"2004","journal-title":"J. Glaucoma"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/12210\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:22:41Z","timestamp":1760127761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/12210"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,30]]},"references-count":39,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241512210"],"URL":"https:\/\/doi.org\/10.3390\/ijms241512210","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,30]]}}}