{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:25:16Z","timestamp":1787117116262,"version":"build-2736575974"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Thyroid eye disease (TED) is a debilitating condition characterized by orbital fibroblast (OF) activation and excessive hyaluronan (HA) accumulation within the retroocular space. While IGF-1R blockade has significantly advanced TED management, incomplete clinical responses and disease relapse underscore the need to identify alternative targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed high-throughput RNA sequencing on primary human TED OFs compared with non-TED controls, followed by pathway enrichment analysis and confirmation of select targets by RT-qPCR. We also performed computational drug repositioning using the TED OF gene signature. Candidate therapeutic activity was validated using functional assays measuring AKT phosphorylation, gene expression, and HA synthesis in primary TED OFs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our analysis identified enrichment of pathways critical to the TED phenotype, including PI3K-AKT signaling, the platelet-derived growth factor (PDGF) pathway, and extracellular matrix remodeling. We validated several key upregulated mediators that may contribute to orbital remodeling, including FOXC2, HGF, MET, HMGA2, and PLEKHG5, alongside the downregulation of the Wnt antagonist SFRP2. We identified sorafenib, which targets VEGFR, PDGFR, and RAF, as a leading candidate to counteract the TED-specific gene signature. Functional assays demonstrated that sorafenib dose-dependently inhibited PDGF\u03b2-induced AKT phosphorylation, gene expression, and significantly attenuated PDGF\u03b2-induced HA synthesis in primary TED OFs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results define a persistent, receptor tyrosine kinase-driven program in orbital fibroblasts obtained from TED and provide a molecular rationale for repurposing sorafenib as a therapeutic strategy for patients with refractory or relapsing TED.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1870087","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:39:32Z","timestamp":1787114372000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic profiling of thyroid eye disease orbital 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United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Ushchak","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Rochester Medical Center","place":["Rochester, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Roztocil","sequence":"additional","affiliation":[{"name":"Flaum Eye Institute, University of Rochester Medical Center","place":["Rochester, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven E.","family":"Feldon","sequence":"additional","affiliation":[{"name":"University of Rochester School of Medicine and Dentistry","place":["Rochester, NY, United States"]},{"name":"Flaum Eye Institute, University of Rochester Medical Center","place":["Rochester, NY, United States"]},{"name":"Center for Visual Sciences, University of Rochester Medical Center","place":["Rochester, NY, United 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