Transcriptomic Profiling of Thyroid Eye Disease Orbital Fat Demonstrates Differences in Adipogenicity and IGF-1R Pathway

Despite recent advances in the treatment of thyroid eye disease (TED), significant gaps remain in our understanding of the underlying molecular mechanisms, particularly concerning the insulin-like growth factor-1 receptor (IGF-1R) pathway. To dissect the pathophysiology of TED, we utilized single nucleus RNA-Seq to analyze orbital fat specimens from both TED patients and matched controls. The analysis demonstrated a marked increase in the proportion of fibroblasts transitioning to adipogenesis in the orbital fat of TED patients compared to controls. This was associated with diverse alterations in immune cell composition. Significant alterations in the IGF-1R signaling pathway were noted between TED specimens and controls, indicating a potential pathological mechanism driven by IGF-1R signaling abnormalities. Additionally, our data show that linsitinib, a small molecule inhibitor of IGF-1R, effectively reduces adipogenesis in TED orbital fibroblasts in vitro, suggesting its potential utility as a therapeutic agent. Our findings reveal that beyond immune dysfunction, abnormal IGF-1R signaling leading to enhanced adipogenesis is a crucial pathogenic mechanism in TED. ### Competing Interest Statement FR has the following relevant disclosures: Amgen - Consultant/Advisor (ended), Immunovant - Researcher (not ended), Acelyrin - Consultant/Advisor (ended), Roche - Researcher (not ended), Viridian - Researcher (not ended). SB has the following relevant disclosures: Genentech - Researcher (not ended), Bayer - Researcher (ended), CDI Labs - co-founder, shareholder, and Scientific Advisory Board member.