{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:02:06Z","timestamp":1791928926140,"version":"4.3.4"},"reference-count":50,"publisher":"Association for Research in Vision and Ophthalmology (ARVO)","issue":"9","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Invest. Ophthalmol. Vis. Sci."],"published-print":{"date-parts":[[2025,7,30]]},"DOI":"10.1167\/iovs.66.9.68","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:00:43Z","timestamp":1753876843000},"page":"68","source":"Crossref","is-referenced-by-count":4,"title":["Epac1 Inhibits Orbital Fibroblast Activation to Ameliorate Thyroid-Associated Orbitopathy-Like Features Through the JAK\/STAT Signaling Pathway"],"prefix":"10.1167","volume":"66","author":[{"given":"Rong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"},{"name":"Hubei Key Laboratory of Otolaryngologic and Ophthalmic Diseases, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Xin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunguo","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"},{"name":"Hubei Key Laboratory of Otolaryngologic and Ophthalmic Diseases, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinmin","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"},{"name":"Hubei Key Laboratory of Otolaryngologic and Ophthalmic Diseases, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenmian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"},{"name":"Hubei Key Laboratory of Otolaryngologic and Ophthalmic Diseases, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ban","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"},{"name":"Hubei Key Laboratory of Otolaryngologic and Ophthalmic Diseases, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"27","reference":[{"issue":"2","key":"bib1","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1007\/s40618-021-01663-9","article-title":"2021 update on thyroid-associated ophthalmopathy","volume":"45","author":"Neag","year":"2022","journal-title":"J Endocrinol Invest"},{"issue":"1","key":"bib2","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1159\/000443828","article-title":"The 2016 European Thyroid Association\/European Group on Graves\u2019 Orbitopathy Guidelines for the Management of Graves\u2019 Orbitopathy","volume":"5","author":"Bartalena","year":"2016","journal-title":"Eur Thyroid J"},{"issue":"11","key":"bib3","doi-asserted-by":"publisher","first-page":"4336","DOI":"10.1210\/en.2015-1399","article-title":"Pentraxin-3 Is a TSH-inducible protein in human fibrocytes and orbital fibroblasts","volume":"156","author":"Wang","year":"2015","journal-title":"Endocrinology"},{"issue":"12","key":"bib4","doi-asserted-by":"publisher","first-page":"3189","DOI":"10.1016\/j.ajpath.2016.08.017","article-title":"The Aryl hydrocarbon receptor and its ligands inhibit myofibroblast formation and activation: implications for thyroid eye disease","volume":"186","author":"Woeller","year":"2016","journal-title":"Am J Pathol"},{"issue":"2","key":"bib5","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1016\/S0021-9258(19)77423-7","article-title":"Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles","volume":"232","author":"Sutherland","year":"1958","journal-title":"J Biol Chem"},{"issue":"4","key":"bib6","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1007\/s00424-009-0747-y","article-title":"Role of the cAMP-binding protein Epac in cardiovascular physiology and pathophysiology","volume":"459","author":"Metrich","year":"2010","journal-title":"Pflugers Arch"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"175645","DOI":"10.1016\/j.ejphar.2023.175645","article-title":"Epac as a tractable therapeutic target","volume":"945","author":"Slika","year":"2023","journal-title":"Eur J Pharmacol"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.jss.2019.12.026","article-title":"Downregulation of Epac reduces fibrosis and induces apoptosis through Akt signaling in human keloid fibroblasts","volume":"257","author":"Lv","year":"2021","journal-title":"J Surg Res"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"611","DOI":"10.2147\/JIR.S296382","article-title":"The potentially therapeutic role of EPAC in curbing the process of idiopathic pulmonary fibrosis via differential cellular pathways","volume":"14","author":"Cao","year":"2021","journal-title":"J Inflamm Res"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/978-981-13-8871-2","article-title":"A glimpse of the mechanisms related to renal fibrosis in diabetic nephropathy","volume":"1165","author":"Zeng","year":"2019","journal-title":"Adv Exp Med Biol"},{"issue":"2","key":"bib11","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1124\/jpet.117.241646","article-title":"Upregulation of Epac-1 in hepatic stellate cells by prostaglandin E(2) in liver fibrosis is associated with reduced fibrogenesis","volume":"363","author":"Schippers","year":"2017","journal-title":"J Pharmacol Exp Ther"},{"issue":"1","key":"bib12","doi-asserted-by":"publisher","first-page":"69","DOI":"10.3390\/cells9010069","article-title":"The role of cyclic AMP signaling in cardiac fibrosis","volume":"9","author":"Delaunay","year":"2019","journal-title":"Cells"},{"issue":"2","key":"bib13","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/s11302-017-9600-5","article-title":"Epac is required for exogenous and endogenous stimulation of adenosine A(2B) receptor for inhibition of angiotensin II-induced collagen synthesis and myofibroblast differentiation","volume":"14","author":"Phosri","year":"2018","journal-title":"Purinergic Signal"},{"issue":"13","key":"bib14","doi-asserted-by":"publisher","first-page":"2599","DOI":"10.1242\/jcs.185629","article-title":"EPAC1 activation by cAMP stabilizes CFTR at the membrane by promoting its interaction with NHERF1","volume":"129","author":"Lobo","year":"2016","journal-title":"J Cell Sci"},{"issue":"11","key":"bib15","doi-asserted-by":"publisher","first-page":"7759","DOI":"10.1002\/jcp.30459","article-title":"GPCR-mediated YAP\/TAZ inactivation in fibroblasts via EPAC1\/2, RAP2C, and MAP4K7","volume":"236","author":"Choi","year":"2021","journal-title":"J Cell Physiol"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"114760","DOI":"10.1016\/j.bcp.2021.114760","article-title":"Targeting the JAK-STAT pathway in autoimmune diseases and cancers: a focus on molecular mechanisms and therapeutic potential","volume":"193","author":"Tzeng","year":"2021","journal-title":"Biochem Pharmacol"},{"issue":"2","key":"bib17","doi-asserted-by":"publisher","first-page":"105607","DOI":"10.1016\/j.jbc.2023.105607","article-title":"TMEM2 inhibits the development of Graves' orbitopathy through the JAK-STAT signaling pathway","volume":"300","author":"Li","year":"2024","journal-title":"J Biol Chem"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"111488","DOI":"10.1016\/j.biopha.2021.111488","article-title":"Epac-1\/Rap-1 signaling pathway orchestrates the reno-therapeutic effect of ticagrelor against renal ischemia\/reperfusion model","volume":"139","author":"El-Mokadem","year":"2021","journal-title":"Biomed Pharmacother"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.yjmcc.2017.05.014","article-title":"Cardiac overexpression of Epac1 in transgenic mice rescues lipopolysaccharide-induced cardiac dysfunction and inhibits Jak-STAT pathway","volume":"108","author":"Jin","year":"2017","journal-title":"J Mol Cell Cardiol"},{"issue":"8","key":"bib20","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1038\/nprot.2016.081","article-title":"High-mass-resolution MALDI mass spectrometry imaging of metabolites from formalin-fixed paraffin-embedded tissue","volume":"11","author":"Ly","year":"2016","journal-title":"Nat Protoc"},{"issue":"2","key":"bib21","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1007\/s40618-022-01902-7","article-title":"The role and molecular mechanism of gut microbiota in Graves\u2019 orbitopathy","volume":"46","author":"Li","year":"2023","journal-title":"J Endocrinol Invest"},{"issue":"3","key":"bib22","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1167\/iovs.66.3.5","article-title":"Butyrate ameliorates Graves' orbitopathy through regulating orbital fibroblast phenotypes and gut microbiota","volume":"66","author":"Ouyang","year":"2025","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"7","key":"bib23","doi-asserted-by":"publisher","first-page":"3091","DOI":"10.1167\/iovs.08-2443","article-title":"Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts: a potential treatment for Graves\u2019 ophthalmopathy","volume":"50","author":"van Steensel","year":"2009","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"2","key":"bib24","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1152\/physrev.00025.2017","article-title":"Intracellular cAMP sensor EPAC: physiology, pathophysiology, and therapeutics development","volume":"98","author":"Robichaux","year":"2018","journal-title":"Physiol Rev"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"104307","DOI":"10.1016\/j.phrs.2019.104307","article-title":"Cryptotanshinone protects against pulmonary fibrosis through inhibiting Smad and STAT3 signaling pathways","volume":"147","author":"Zhang","year":"2019","journal-title":"Pharmacol Res"},{"issue":"6","key":"bib26","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.3390\/ijms20061396","article-title":"Deletion of osteopontin enhances \u00df2-adrenergic receptor-dependent anti-fibrotic signaling in cardiomyocytes","volume":"20","author":"Pollard","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"2","key":"bib27","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1111\/j.1476-5381.2012.01847.x","article-title":"cAMP and Epac in the regulation of tissue fibrosis","volume":"166","author":"Insel","year":"2012","journal-title":"Br J Pharmacol"},{"issue":"8","key":"bib28","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1248\/bpb.b21-01057","article-title":"Selexipag improves lipopolysaccharide-induced ARDS on C57BL\/6 mice by modulating the cAMP\/PKA and cAMP\/Epac1 signaling pathways","volume":"45","author":"Chen","year":"2022","journal-title":"Biol Pharm Bull"},{"issue":"3","key":"bib29","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1038\/s41401-021-00689-2","article-title":"Epac activation ameliorates tubulointerstitial inflammation in diabetic nephropathy","volume":"43","author":"Yang","year":"2022","journal-title":"Acta Pharmacol Sin"},{"issue":"3","key":"bib30","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1167\/iovs.66.3.33","article-title":"Orbital clinicopathological differences in thyroid eye disease: an analysis of cytokines with histopathological and clinical correlation","volume":"66","author":"Li","year":"2025","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"1","key":"bib31","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1093\/cvr\/cvy173","article-title":"Exchange protein activated by cyclic-adenosine monophosphate (Epac) regulates atrial fibroblast function and controls cardiac remodelling","volume":"115","author":"Surinkaew","year":"2019","journal-title":"Cardiovasc Res"},{"issue":"9","key":"bib32","doi-asserted-by":"publisher","first-page":"2028","DOI":"10.1016\/j.ophtha.2016.05.052","article-title":"Orbital angiogenesis and lymphangiogenesis in thyroid eye disease: an analysis of vascular growth factors with clinical correlation","volume":"123","author":"Wong","year":"2016","journal-title":"Ophthalmology"},{"issue":"1","key":"bib33","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1210\/jc.2009-1614","article-title":"Increased generation of fibrocytes in thyroid-associated ophthalmopathy","volume":"95","author":"Douglas","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"7453260","DOI":"10.1155\/2019\/7453260","article-title":"Immunological aspects of Graves\u2019 ophthalmopathy","volume":"2019","author":"Lacheta","year":"2019","journal-title":"Biomed Res Int"},{"issue":"12","key":"bib35","doi-asserted-by":"publisher","first-page":"1666","DOI":"10.3390\/biom10121666","article-title":"Transforming growth factor-\u00df signaling in fibrotic diseases and cancer-associated fibroblasts","volume":"10","author":"Shi","year":"2020","journal-title":"Biomolecules"},{"issue":"4","key":"bib36","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1167\/iovs.03-0660","article-title":"Involvement of CTGF in TGF-beta1-stimulation of myofibroblast differentiation and collagen matrix contraction in the presence of mechanical stress","volume":"45","author":"Garrett","year":"2004","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"7","key":"bib37","doi-asserted-by":"publisher","first-page":"3011","DOI":"10.1167\/iovs.16-20633","article-title":"Transforming growth factor \u00df1-induced NADPH oxidase-4 expression and fibrotic response in conjunctival fibroblasts","volume":"58","author":"Brown","year":"2017","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"1","key":"bib38","doi-asserted-by":"publisher","first-page":"7276","DOI":"10.1038\/s41598-018-25370-3","article-title":"Essential role of connective tissue growth factor (CTGF) in transforming growth factor-beta1 (TGF-beta1)-induced myofibroblast transdifferentiation from Graves\u2019 orbital fibroblasts","volume":"8","author":"Tsai","year":"2018","journal-title":"Sci Rep"},{"issue":"98","key":"bib39","doi-asserted-by":"publisher","first-page":"13556","DOI":"10.1039\/D2CC04825F","article-title":"Myofibroblast specific targeting approaches to improve fibrosis treatment","volume":"58","author":"Beaven","year":"2022","journal-title":"Chem Commun (Camb)"},{"issue":"11","key":"bib40","doi-asserted-by":"publisher","first-page":"6951","DOI":"10.1074\/jbc.M114.606186","article-title":"Myofibroblasts exhibit enhanced fibronectin assembly that is intrinsic to their contractile phenotype","volume":"290","author":"Torr","year":"2015","journal-title":"J Biol Chem"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"7010196","DOI":"10.1155\/2018\/7010196","article-title":"Thyroid-associated orbitopathy and biomarkers: where we are and what we can hope for the future","volume":"2018","author":"Turck","year":"2018","journal-title":"Dis Markers"},{"issue":"6","key":"bib42","doi-asserted-by":"publisher","first-page":"e100","DOI":"10.1038\/emm.2014.26","article-title":"Benzylideneacetophenone derivatives attenuate IFN-gamma-induced IP-10\/CXCL10 production in orbital fibroblasts of patients with thyroid-associated ophthalmopathy through STAT-1 inhibition","volume":"46","author":"Lee","year":"2014","journal-title":"Exp Mol Med"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"4923","DOI":"10.12659\/MSM.917299","article-title":"Research on the potential mechanism of gypenosides on treating thyroid-associated ophthalmopathy based on network pharmacology","volume":"25","author":"Li","year":"2019","journal-title":"Med Sci Monit"},{"issue":"1","key":"bib44","doi-asserted-by":"publisher","first-page":"L127","DOI":"10.1152\/ajplung.00448.2018","article-title":"Organic dust induces inflammatory gene expression in lung epithelial cells via ROS-dependent STAT-3 activation","volume":"317","author":"Natarajan","year":"2019","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"issue":"2","key":"bib45","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1089\/thy.2016.0397","article-title":"Antioxidant actions of selenium in orbital fibroblasts: a basis for the effects of selenium in Graves\u2019 orbitopathy","volume":"27","author":"Rotondo Dottore","year":"2017","journal-title":"Thyroid"},{"issue":"7","key":"bib46","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1007\/s40618-017-0809-5","article-title":"Antioxidant effects of beta-carotene, but not of retinol and vitamin E, in orbital fibroblasts from patients with Graves\u2019 orbitopathy (GO)","volume":"41","author":"Rotondo Dottore","year":"2018","journal-title":"J Endocrinol Invest"},{"issue":"11","key":"bib47","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1016\/j.chembiol.2006.09.018","article-title":"Stattic: a small-molecule inhibitor of STAT3 activation and dimerization","volume":"13","author":"Schust","year":"2006","journal-title":"Chem Biol"},{"issue":"6","key":"bib48","doi-asserted-by":"publisher","first-page":"3288","DOI":"10.3390\/ijms25063288","article-title":"The role of fibrogenesis and extracellular matrix proteins in the pathogenesis of Graves\u2019","volume":"25","author":"Chiu","year":"2024","journal-title":"Ophthalmopathy Int J Mol Sci"},{"issue":"1","key":"bib49","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.cellsig.2015.10.009","article-title":"cAMP\/PKA enhances interleukin-1\u00df-induced interleukin-6 synthesis through STAT3 in glial cells","volume":"28","author":"Tanabe","year":"2016","journal-title":"Cell Signal"},{"issue":"9","key":"bib50","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1167\/iovs.62.9.24","article-title":"Transcriptomic profiling of control and thyroid-associated orbitopathy (TAO) orbital fat and TAO orbital fibroblasts undergoing adipogenesis","volume":"62","author":"Kim","year":"2021","journal-title":"Invest Ophthalmol Vis Sci"}],"container-title":["Investigative Ophthalmology &amp; Visual Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/iovs.arvojournals.org\/article.aspx?articleid=2810606","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:32:10Z","timestamp":1791927130000},"score":1,"resource":{"primary":{"URL":"https:\/\/iovs.arvojournals.org\/article.aspx?articleid=2810606"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,30]]},"references-count":50,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,7,1]]}},"URL":"https:\/\/doi.org\/10.1167\/iovs.66.9.68","relation":{},"ISSN":["1552-5783"],"issn-type":[{"value":"1552-5783","type":"print"}],"subject":[],"published":{"date-parts":[[2025,7,30]]}}}