S-phase kinase-associated protein 1 inhibits orbital fibroblasts adipogenesis to improve thyroid-associated ophthalmopathy (TAO)

Abstract

Thyroid-associated ophthalmopathy (TAO), a localized manifestation of Graves' disease, involves complex autoimmune interactions leading to orbital tissue inflammation and remodeling. The pathophysiology of TAO is marked by significant orbital connective tissue and fat pad expansion, mononuclear cell infiltration, and fibrosis, ultimately affecting eye motility and quality of life. This study explores the role of S-phase kinase-associated protein 1 (SKP1) in the adipogenic differentiation of orbital fibroblasts (OFs), a key process in TAO. Using bioinformatics analysis of gene expression profiles from TAO patients (GSE105149 and GSE58331), SKP1 was identified as a critical regulator of adipogenesis. Experimental validation confirmed that SKP1 expression is significantly downregulated in TAO-derived OFs under adipogenic differentiation for 10 days, correlating with elevated lipid accumulation and increased expression levels of adipogenic markers. Furthermore, downregulation of SKP1 promotes adipogenic differentiation, while upregulation inhibits this process in OFs in vitro and in TAO mice models in vivo. Mechanistically, SKP1 was shown to modulate the PI3K/AKT signaling, with downregulation activating and upregulation inhibiting the pathway, thereby influencing adipogenesis. In summary, SKP1 exerts a crucial regulatory effect on TAO pathogenesis and might act as an underlying therapeutic target for mitigating OFs adipogenesis in TAO.