{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T12:53:14Z","timestamp":1790945594487,"version":"4.1.0"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>\n                      The insulin-like growth factor-1 receptor (IGF-1R) and its downstream signaling pathways drive proliferation, survival, and extracellular matrix production, representing key therapeutic targets in thyroid eye disease (TED). This novel\n                      <jats:italic>in vitro<\/jats:italic>\n                      study investigated the inhibitory effects of the dual IGF-1R\/insulin receptor small-molecule inhibitor Linsitinib on orbital target cell activity, proliferation, and survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human orbital fibroblasts (OF) were pre-treated with increasing doses of Linsitinib and stimulated with 100 ng\/mL IGF-1 to quantify hyaluronic acid (HA) and pro-collagen in supernatants via ELISA. Intracellular protein kinase B (AKT) phosphorylation at Serine 473 was quantified in cell lysates. Additionally, an equimolar comparison between Linsitinib and the anti-IGF-1R monoclonal antibody Teprotumumab was performed in IGF-1R-expressing cells. Proliferation was assessed both microscopically and by tetrazolium assay, while apoptosis was evaluated by caspase-3\/7 activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Linsitinib markedly suppressed IGF-1-induced HA and pro-collagen secretion, with TED OF showing significantly greater sensitivity and exclusive morphological evidence of apoptosis compared to control OF. Linsitinib effectively inhibited IGF-1-induced AKT phosphorylation to baseline levels in OF. Equimolar comparison in IGF-1R-expressing cells demonstrated that Linsitinib outperformed Teprotumumab in inhibiting cell proliferation across most tested concentrations, whereas Teprotumumab showed higher potency only at the lowest concentrations. While Teprotumumab failed to induce cell death, Linsitinib triggered robust activity of the apoptosis markers caspase-3\/7. Morphologically, in contrast to Teprotumumab, Linsitinib induced dose-dependent changes characterized by cellular contraction and formation of gaps in the monolayer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Linsitinib reverses OF activation through intracellular kinase blockade while outperforming Teprotumumab in equimolar comparison. These findings highlight the role of Linsitinib as a potent, dual-targeted therapy for TED.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1920590","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T11:54:35Z","timestamp":1790942075000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The dual IGF-1R\/IR blocker, Linsitinib, modulates human orbital fibroblast activity and proliferation"],"prefix":"10.3389","volume":"17","author":[{"given":"Maximilian","family":"Luffy","sequence":"first","affiliation":[{"name":"Molecular Thyroid Research Laboratory, Department of Medicine I, Johannes Gutenberg-University (JGU) Medical Center","place":["Mainz, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Wagner","sequence":"additional","affiliation":[{"name":"Molecular Thyroid Research Laboratory, Department of Medicine I, 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