{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:46:59Z","timestamp":1787021219808,"version":"build-2736575974"},"reference-count":36,"publisher":"The Endocrine Society","issue":"8","license":[{"start":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:00:00Z","timestamp":1733097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82200876"],"award-info":[{"award-number":["82200876"]}],"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":["81870557"],"award-info":[{"award-number":["81870557"]}],"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":["81572624"],"award-info":[{"award-number":["81572624"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2024A1515013290"],"award-info":[{"award-number":["2024A1515013290"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015956","name":"Key Field Research and Development Program of Guangdong Province, China","doi-asserted-by":"publisher","award":["2019B020230001"],"award-info":[{"award-number":["2019B020230001"]}],"id":[{"id":"10.13039\/501100015956","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"publisher","award":["2020A1515010049"],"award-info":[{"award-number":["2020A1515010049"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Thyroid eye disease (TED) is a challenging condition owing to relentless orbital tissue remodeling, with thyrotropin receptor (TSHR) in orbital fibroblasts (OFs) serving as a promising therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study seeks to discover potential TSHR inhibitors among US Food and Drug Administration (FDA)-approved drugs and evaluate their effects on TED-OFs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Adipose tissues were sourced from the patients with or without TED. Isolated OFs were cultivated in proliferation medium or stimulated for adipogenic\/fibrotic differentiation in 2-dimensional\/3-dimenstional models, treated with 2\u2032-O-galloylhyperin (2\u2032-O-GH) (0, 5, 20, and 50\u2005\u03bcM). Using structure-based virtual screening (SBVS), potential TSHR antagonists were identified. Cellular proliferation was analyzed by 5-ethynyl-2\u2032-deoxyuridine (EdU) incorporation, flow cytometry, and spheroid size. Adipogenesis was determined by Oil Red O staining, Western blot, and immunofluorescence (IF). Fibrosis was assessed using wound\u2013healing assays, Western blot and IF. Cyclic adenosine monophosphate (cAMP), hyaluronan (HA), and cytokine were quantified by enzyme-linked immunosorbent assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Herein, the FDA-approved drug 2\u2032-O-GH dose-dependently decreased cAMP production and the subsequent cAMP-response element binding protein (CREB) phosphorylation stimulated by a TSHR-stimulating monoclonal autoantibody M22, which was reversed by a consistently activated mutation of TSHR (L629F). As expected, 2\u2032-O-GH attenuated lipid accumulation in TED-OFs, along with downregulation of key adipogenic markers, and 2\u2032-O-GH ameliorated HA production during adipogenesis. Notably, 2\u2032-O-GH dampened wound closure and fibrotic differentiation of TED-OF stimulated by transforming growth factor beta 1. Correspondingly, proliferation of TED-OFs was halted by 2\u2032-O-GH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>2\u2032-O-GH is promising for prevention of tissue remodeling of TED by exerting inhibitory effects on proliferation, differentiation, and HA deposition by inhibiting TSHR activation, implying its potential therapeutic value for TED.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgae732","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T07:38:38Z","timestamp":1732001918000},"page":"e2711-e2722","source":"Crossref","is-referenced-by-count":2,"title":["2\u2032-O-Galloylhyperin Prevents Tissue Remodeling in Thyroid Eye Disease: Prospects as a Thyrotropin Receptor Antagonist"],"prefix":"10.1210","volume":"110","author":[{"given":"Yan","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, Guangdong, 510080 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, Guangdong, 510080 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, Guangdong, 510080 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanglei","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, Guangdong, 510080 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, Guangdong, 510080 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, Guangdong, 510080 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4188-336X","authenticated-orcid":false,"given":"Haipeng","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, Guangdong, 510080 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3782-9210","authenticated-orcid":false,"given":"Yanbing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, Guangdong, 510080 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2024,12,2]]},"reference":[{"issue":"2","key":"2025071507131058000_dgae732-B1","first-page":"185","article-title":"Graves\u2019 disease","volume":"376","author":"Smith","year":"2017","journal-title":"N Engl J Med"},{"issue":"3","key":"2025071507131058000_dgae732-B2","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.ajo.2011.02.018","article-title":"Quality of life in a German graves orbitopathy population","volume":"152","author":"Ponto","year":"2011","journal-title":"Am J Ophthalmol"},{"key":"2025071507131058000_dgae732-B3","doi-asserted-by":"crossref","first-page":"615993","DOI":"10.3389\/fendo.2020.615993","article-title":"Natural history, risk factors, and prevention of Graves\u2019 orbitopathy","volume":"11","author":"Bartalena","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2025071507131058000_dgae732-B4","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.exer.2015.02.007","article-title":"Current perspectives on the role of orbital fibroblasts in the pathogenesis of Graves\u2019 ophthalmopathy","volume":"142","author":"Dik","year":"2016","journal-title":"Exp Eye Res"},{"issue":"11","key":"2025071507131058000_dgae732-B5","doi-asserted-by":"crossref","first-page":"E1727","DOI":"10.1210\/jc.2011-1156","article-title":"A novel mechanism involved in the pathogenesis of Graves ophthalmopathy (GO): clathrin is a possible targeting molecule for inhibiting local immune response in the orbit","volume":"96","author":"Meyer zu Horste","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2025071507131058000_dgae732-B6","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1530\/EJE-14-1140","article-title":"Some studies on the natural history of Graves\u2019 orbitopathy: increase in orbital fat is a rather late phenomenon","volume":"173","author":"Potgieser","year":"2015","journal-title":"Eur J Endocrinol"},{"issue":"2","key":"2025071507131058000_dgae732-B7","doi-asserted-by":"crossref","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":"2025071507131058000_dgae732-B8","first-page":"90","article-title":"Graves\u2019 autoantibodies exhibit different stimulating activities in cultures of thyrocytes and orbital fibroblasts not reflected by clinical assays","volume":"32","author":"Krieger","year":"2022","journal-title":"Thyroid"},{"key":"2025071507131058000_dgae732-B9","doi-asserted-by":"crossref","first-page":"107502","DOI":"10.1016\/j.pharmthera.2020.107502","article-title":"TSH\/IGF1 receptor crosstalk: mechanism and clinical implications","volume":"209","author":"Krieger","year":"2020","journal-title":"Pharmacol Ther"},{"issue":"12","key":"2025071507131058000_dgae732-B10","doi-asserted-by":"crossref","first-page":"E1569","DOI":"10.1152\/ajpendo.00572.2011","article-title":"Expression of functional TSH receptor in white adipose tissues of hyt\/hyt mice induces lipolysis in vivo","volume":"302","author":"Endo","year":"2012","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"10","key":"2025071507131058000_dgae732-B11","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1055\/s-0035-1559648","article-title":"Mechanisms of action of TSHR autoantibodies","volume":"47","author":"Furmaniak","year":"2015","journal-title":"Horm Metab Res"},{"issue":"7","key":"2025071507131058000_dgae732-B12","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1089\/thy.2019.0036","article-title":"Antigen-specific immunotherapy with thyrotropin receptor peptides in graves\u2019 hyperthyroidism: a phase i study","volume":"29","author":"Pearce","year":"2019","journal-title":"Thyroid"},{"issue":"2","key":"2025071507131058000_dgae732-B13","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1089\/thy.2018.0326","article-title":"Therapeutic effects of short cyclic and combined epitope peptides in a long-term model of Graves\u2019 disease and orbitopathy","volume":"29","author":"Fassbender","year":"2019","journal-title":"Thyroid"},{"issue":"1","key":"2025071507131058000_dgae732-B14","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1210\/en.2013-1835","article-title":"A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice","volume":"155","author":"Neumann","year":"2014","journal-title":"Endocrinology"},{"key":"2025071507131058000_dgae732-B15","doi-asserted-by":"crossref","first-page":"130","DOI":"10.3389\/fendo.2016.00130","article-title":"TSH receptor signaling abrogation by a novel small molecule","volume":"7","author":"Latif","year":"2016","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"1","key":"2025071507131058000_dgae732-B16","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1089\/thy.2018.0349","article-title":"A new highly thyrotropin receptor-selective small-molecule antagonist with potential for the treatment of Graves\u2019 orbitopathy","volume":"29","author":"Marcinkowski","year":"2019","journal-title":"Thyroid"},{"issue":"6","key":"2025071507131058000_dgae732-B17","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1089\/thy.2022.0694","article-title":"Thyrotropin receptor antagonism by a novel small molecule: preclinical in vitro observations","volume":"33","author":"Kahaly","year":"2023","journal-title":"Thyroid"},{"issue":"7607","key":"2025071507131058000_dgae732-B18","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/534314a","article-title":"Can you teach old drugs new tricks?","volume":"534","author":"Nosengo","year":"2016","journal-title":"Nature"},{"issue":"6","key":"2025071507131058000_dgae732-B19","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1210\/clinem\/dgaa161","article-title":"Novel roles of chloroquine and hydroxychloroquine in graves\u2019 orbitopathy therapy by targeting orbital fibroblasts","volume":"105","author":"Guo","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2025071507131058000_dgae732-B20","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s41419-024-06514-y","article-title":"Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL","volume":"15","author":"Li","year":"2024","journal-title":"Cell Death Dis"},{"issue":"8","key":"2025071507131058000_dgae732-B21","first-page":"2695","article-title":"Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic thyroid adenomas","volume":"82","author":"Parma","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2025071507131058000_dgae732-B22","unstructured":"Guo Y, Liu B, Liang W, et al \u00a0Supplementary material for 2\u2032-O-galloylhyperin prevents tissue remodeling in thyroid eye disease: prospects as a thyrotropin receptor antagonist. Dryad, Dataset. 10.5061\/dryad.1rn8pk13p."},{"issue":"4","key":"2025071507131058000_dgae732-B23","doi-asserted-by":"crossref","first-page":"106451","DOI":"10.1016\/j.isci.2023.106451","article-title":"Steroidogenic factor 1 protects mice from obesity-induced glucose intolerance via improving glucose-stimulated insulin secretion by beta cells","volume":"26","author":"Guo","year":"2023","journal-title":"iScience"},{"issue":"3","key":"2025071507131058000_dgae732-B24","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.3390\/cimb43030126","article-title":"Expression of endogenous putative TSH binding protein in orbit","volume":"43","author":"Draman","year":"2021","journal-title":"Curr Issues Mol Biol"},{"key":"2025071507131058000_dgae732-B25","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.cbi.2019.02.029","article-title":"2\u2032O-galloylhyperin attenuates LPS-induced acute lung injury via up-regulation antioxidation and inhibition of inflammatory responses in vivo","volume":"304","author":"Zhang","year":"2019","journal-title":"Chem Biol Interact"},{"key":"2025071507131058000_dgae732-B26","doi-asserted-by":"crossref","first-page":"679","DOI":"10.3389\/fphar.2018.00679","article-title":"2\u2032-O-Galloylhyperin isolated from Pyrola incarnata fisch. Attenuates LPS-induced inflammatory response by activation of SIRT1\/Nrf2 and inhibition of the NF-kappaB pathways in vitro and vivo","volume":"9","author":"Wang","year":"2018","journal-title":"Front Pharmacol"},{"key":"2025071507131058000_dgae732-B27","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.fct.2017.02.016","article-title":"Hepatoprotective effect of 2\u2032-O-galloylhyperin against oxidative stress-induced liver damage through induction of Nrf2\/ARE-mediated antioxidant pathway","volume":"102","author":"Wang","year":"2017","journal-title":"Food Chem Toxicol"},{"issue":"4","key":"2025071507131058000_dgae732-B28","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/S1534-5807(04)00075-9","article-title":"Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment","volume":"6","author":"McBeath","year":"2004","journal-title":"Dev Cell"},{"issue":"7","key":"2025071507131058000_dgae732-B29","doi-asserted-by":"crossref","first-page":"e28397","DOI":"10.1016\/j.heliyon.2024.e28397","article-title":"Comparison of orbital fibroblasts from Graves\u2019 ophthalmopathy and healthy control","volume":"10","author":"Wu","year":"2024","journal-title":"Heliyon"},{"issue":"Suppl 1","key":"2025071507131058000_dgae732-B30","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1159\/000511871","article-title":"Modulating TSH receptor signaling for therapeutic benefit","volume":"9","author":"Krause","year":"2020","journal-title":"Eur Thyroid J"},{"issue":"8","key":"2025071507131058000_dgae732-B31","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1002\/bmc.3117","article-title":"Validated LC-MS\/MS method for the simultaneous determination of hyperoside and 2\u2032'-O-galloylhyperin in rat plasma: application to a pharmacokinetic study in rats","volume":"28","author":"Zhou","year":"2014","journal-title":"Biomed Chromatogr"},{"issue":"2","key":"2025071507131058000_dgae732-B32","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1097\/00002341-199306000-00001","article-title":"The association of cigarette smoking with clinical subtypes of ophthalmic Graves\u2019 disease","volume":"9","author":"Nunery","year":"1993","journal-title":"Ophthalmic Plast Reconstr Surg"},{"issue":"1","key":"2025071507131058000_dgae732-B33","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S1542-0124(12)70215-X","article-title":"Ocular surface effects of thyroid disease","volume":"8","author":"Sokol","year":"2010","journal-title":"Ocul Surf"},{"issue":"5","key":"2025071507131058000_dgae732-B34","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3109\/01676830.2014.937877","article-title":"Cytokine profiles in clinical subtypes of ophthalmic Graves\u2019 disease","volume":"33","author":"Linquist","year":"2014","journal-title":"Orbit"},{"issue":"12","key":"2025071507131058000_dgae732-B35","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.tcb.2011.09.005","article-title":"From 3D cell culture to organs-on-chips","volume":"21","author":"Huh","year":"2011","journal-title":"Trends Cell Biol"},{"issue":"1","key":"2025071507131058000_dgae732-B36","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1210\/en.2018-00272","article-title":"HIF2A-LOX pathway promotes fibrotic tissue remodeling in thyroid-associated orbitopathy","volume":"160","author":"Hikage","year":"2019","journal-title":"Endocrinology"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgae732\/60933694\/dgae732.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/110\/8\/e2711\/60933694\/dgae732.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/110\/8\/e2711\/60933694\/dgae732.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T11:13:56Z","timestamp":1752578036000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/110\/8\/e2711\/7914954"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,2]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,12,2]]},"published-print":{"date-parts":[[2025,7,15]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgae732","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,8]]},"published":{"date-parts":[[2024,12,2]]}}}