Transcriptomic Profiling of Thyroid Eye Disease Orbital Fibroblasts Identifies Sorafenib as a Novel Therapeutic

Abstract

Thyroid eye disease (TED) is a debilitating condition characterized by orbital fibroblast (OF) activation and excessive hyaluronic acid (HA) accumulation within the retro-ocular space. While IGF-1R blockade with teprotumumab has significantly advanced TED management, incomplete clinical responses and disease relapse underscore the need to identify alternative targets. In this study, we used high-throughput RNA sequencing to map the transcriptomic landscape in TED OFs compared with non-TED OF controls. Our analysis identified robust 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, and HMGA2, alongside the downregulation of the Wnt antagonist SFRP2. By employing a computational drug-repositioning approach, we identified the multi-kinase inhibitor sorafenib, which targets VEGFR, PDGFR, and RAF, as a potent candidate to neutralize the TED-specific gene signature. Functional assays demonstrated that sorafenib dose-dependently inhibited PDGF-induced AKT phosphorylation and significantly attenuated HA synthesis in primary TED OFs. These results define a persistent, receptor tyrosine kinase-driven program in the TED orbit and suggest that multi-kinase inhibition represents a viable therapeutic strategy for refractory TED. HighlightsO_LIThyroid eye disease (TED) orbital fibroblasts exhibit a transcriptomic signature characterized by elevated PI3K/AKT, angiogenic, and growth factor signaling. C_LIO_LIComputational drug prediction identifies sorafenib as a candidate to reverse the TED gene signature. C_LIO_LISorafenib dose-dependently inhibits AKT activation and hyaluronic acid production in TED orbital fibroblasts. C_LI