{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:17:34Z","timestamp":1790727454885,"version":"4.1.0"},"reference-count":40,"publisher":"SAGE Publications","issue":"12","license":[{"start":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T00:00:00Z","timestamp":1701388800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>In Graves' orbitopathy (GO), localized orbital inflammation within the fixed orbit often leads to a fibrotic phenotype resulting in restrictive myopathy or refractory proptosis. However, the molecular pathways related to the transition from inflammation to fibrosis in GO are less understood. Yes-associated protein (YAP) and its homolog, transcriptional coactivator with PDZ-binding motif (TAZ; a Hippo pathway effector), are critical mechanosensors of mechanical stimuli and activate signaling cascades for cell proliferation, differentiation, and transformation. In this study, we aimed to examine the role of YAP in both inflammatory and fibrotic GO pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Based on RNA sequencing performed on freshly obtained orbital adipose tissue from patients with GO and healthy individuals, Gene Ontology analysis and gene set-enrichment analysis were performed to analyze gene-expression differences between GO and normal orbital tissues. The role of YAP in GO-related inflammation and fibrosis was studied in primary cultured orbital fibroblasts. The effects of interleukin-1\u03b2 (IL-1\u03b2)-induced inflammation and transforming growth factor-beta (TGF-\u03b2)-induced fibrosis on YAP expression were evaluated using real-time polymerase chain reaction and Western blotting analyses. The effects of YAP on inflammatory and fibrotic responses were also examined by\n                      <jats:italic toggle=\"yes\">YAP<\/jats:italic>\n                      silencing or treatment with pharmacological YAP inhibitors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      RNA sequencing revealed enhanced\n                      <jats:italic toggle=\"yes\">YAP<\/jats:italic>\n                      expression in GO orbital tissues. Gene Ontology analysis indicated that \u201cresponse to mechanical stimulus\u201d-related genes were overexpressed in GO orbital tissues, along with those enriched for the \u201cadipose proliferation,\u201d \u201cinflammatory responses,\u201d and \u201chormone stimulus responses\u201d terms. IL-1\u03b2 did not enhance YAP expression, and\n                      <jats:italic toggle=\"yes\">YAP<\/jats:italic>\n                      silencing decreased IL-1\u03b2-induced\n                      <jats:italic toggle=\"yes\">IL-6<\/jats:italic>\n                      expression while increasing prostaglandin-endoperoxide synthase 2 expression, leading to paradoxical pro-inflammatory effects. Conversely, TGF-\u03b2 enhanced YAP expression, and\n                      <jats:italic toggle=\"yes\">YAP<\/jats:italic>\n                      silencing and pharmacological YAP inhibitor (cerivastatin, verteporfin, TED-347, and CA3) treatment significantly reduced TGF-\u03b2-induced myofibroblast differentiation and collagen formation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>YAP, a mechanotransducer responding to mechanical stimuli, was strongly expressed in GO orbital tissues, and YAP was induced by TGF-\u03b2 in orbital fibroblasts. Our study establishes YAP as a novel mediator of GO pathobiology, potentially mediating the transition from early inflammation to chronic fibrosis in GO. The finding that YAP inhibition suppressed TGF-\u03b2-induced fibrotic response suggests YAP as a therapeutic target against the fibrotic mechanism of GO.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2023.0309","type":"journal-article","created":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T08:19:43Z","timestamp":1696580383000},"page":"1465-1475","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":20,"title":["Yes-Associated Protein Mediates the Transition from Inflammation to Fibrosis in Graves' Orbitopathy"],"prefix":"10.1177","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3011-7213","authenticated-orcid":false,"given":"JaeSang","family":"Ko","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Severance Hospital, The Institute of Vision Research, Yonsei University College of Medicine, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Joon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Severance Hospital, The Institute of Vision Research, Yonsei University College of Medicine, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Hyun","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Severance Hospital, The Institute of Vision Research, Yonsei University College of Medicine, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher Seungkyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Severance Hospital, The Institute of Vision Research, Yonsei University College of Medicine, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8751-9467","authenticated-orcid":false,"given":"Jin Sook","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Severance Hospital, The Institute of Vision Research, Yonsei University College of Medicine, Seoul, Republic of 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