{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T12:29:57Z","timestamp":1791030597183,"version":"4.1.0"},"reference-count":21,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T00:00:00Z","timestamp":1734480000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Ophthalmology, College of medicine, the Catholic University of Korea, Ki-Soo Kim Research Fund, 2023"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Thyroid-associated ophthalmopathy (TAO), an autoimmune disorder of the retrobulbar tissue, is present in up to 50 percent of Graves\u2019s hyperthyroidism patients. Insulin-like growth factor 1 receptor (IGF-1R) has received attention as a target for the development of therapeutic agent for TAO. IGF-1R and TSHR (thyroid stimulating hormone receptor) interact with each other to form a physical or functional complex, further promoting the development of TAO. Linsitinib, OSI-906, is an inhibitor of IGF-1R and has been reported to inhibit cell proliferation of several tumor cells. Linsitinib has been receiving attention not only for its anticancer effect, but also for its anti-inflammatory effects. It has been reported that linsitinib reduces infiltration of inflammatory cells in orbital tissues, resulting in the reduction of muscle edema and adipose tissues in an experimental murine model for Graves\u2019 disease. In the current study, we investigated the issue of whether linsitinib inhibits the IGF-1-induced proliferation of orbital fibroblasts (OFs) via the suppression of phosphatidylinositol 3-kinase (PI3K) \/ Akt and extracellular signal-regulated kinase (ERK) pathway. Our results showed that pretreatment with linsitinib inhibited IGF-1-induced cell proliferation and hyaluronic acid secretion in the OFs of TAO patients. In addition, our results showed that pretreatment with linsitinib inhibited IGF-1-induced phosphorylation of IGF-1R\u03b2 at Tyr1135, Akt at Ser473, and ERK in the OFs of patients with TAO. These results indicate that linsitinib inhibits IGF-1-induced cell proliferation and hyaluronic acid secretion in the OFs of TAO patients by suppressing the PI3K\/Akt and ERK pathways, validating the use of linsitinib as a novel therapeutic agent for TAO.<\/jats:p>","DOI":"10.1371\/journal.pone.0311093","type":"journal-article","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T13:30:31Z","timestamp":1734528631000},"page":"e0311093","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Linsitinib inhibits IGF-1-induced cell proliferation and hyaluronic acid secretion by suppressing PI3K\/Akt and ERK pathway in orbital fibroblasts from patients with thyroid-associated ophthalmopathy"],"prefix":"10.1371","volume":"19","author":[{"given":"Ji-Young","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2767-6188","authenticated-orcid":true,"given":"Seong-Beom","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3984-9506","authenticated-orcid":true,"given":"Suk-Woo","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1634-2008","authenticated-orcid":true,"given":"Ji-Sun","family":"Paik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,18]]},"reference":[{"issue":"8","key":"pone.0311093.ref001","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1056\/NEJMra0905750","article-title":"Graves\u2019 ophthalmopathy","volume":"362","author":"RS Bahn","year":"2010","journal-title":"N Engl J Med"},{"issue":"6","key":"pone.0311093.ref002","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1210\/er.2002-0020","article-title":"Current perspective on the pathogenesis of Graves\u2019 disease and ophthalmopathy","volume":"24","author":"BS Prabhakar","year":"2003","journal-title":"Endocr Rev"},{"issue":"2","key":"pone.0311093.ref003","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0300-595X(85)80037-2","article-title":"The pathogenesis of Graves\u2019 ophthalmopathy","volume":"14","author":"P. 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