Treatment of Pathological Lymphangiogenesis via Circular RNA-Mediated Cholesterol Metabolism Remodeling.

PURPOSE: Lymphangiogenesis plays important roles in the pathogenesis of human diseases, including inflammatory ocular diseases, metabolic diseases, and cancers, by affecting lipid metabolism and immune homeostasis. Despite growing evidence showing that circular RNAs (circRNAs) act as the regulators of inflammatory and metabolic pathways, their roles in lymphatic dysfunction remain unclear. This study aims to explore the involvement of circRNA-KIF6 (cKIF6) in pathological lymphangiogenesis and elucidate the underlying mechanism. METHODS: The cKIF6 expression was evaluated in mouse-sutured corneas and lymphatic endothelial cells (LECs) isolated from juvenile foreskin under inflammatory conditions. Functional assays, including viability, proliferation, migration, and tube formation, were conducted on LECs after cKIF6 silencing. Lymphangiogenesis was evaluated using mouse-sutured cornea and Matrigel plug models. Mechanistic studies explored the role of cKIF6 as a molecular sponge for miR-582 and its downstream effect on methylsterol monooxygenase 1 (MSMO1). RESULTS: The cKIF6 expression was significantly elevated in mouse-sutured corneas and inflamed LECs. Silencing cKIF6 impaired LEC viability, proliferation, migration, and tube formation, leading to reduced lymphangiogenesis in both in vitro and in vivo models. Mechanistically, cKIF6 acted as a miR-582 sponge, resulting in elevated MSMO1 expression and increased cholesterol content in LECs. The augmented proliferation, migration, and tube formation abilities of cKIF6-overexpressing LECs were attenuated by the inhibitor of cholesterol biosynthesis. CONCLUSIONS: The cKIF6 regulates lymphangiogenesis by targeting cholesterol metabolism, making it a promising therapeutic target for lymphangiogenesis-related diseases.