Abstract
Macrophages play an important role in the development of vascular diseases, with their homeostasis closely linked to metabolic reprogramming. This study aims to explore the role of circular RNA-mediated epigenetic remodeling in maintaining macrophage homeostasis during diabetes-induced microvascular dysfunction. We identified a circular RNA, circRNA-sperm antigen with calponin homology and coiled-coil domains 1 (cSPECC1), which is significantly up-regulated in diabetic retinas and in macrophages under diabetic stress. cSPECC1 knockdown in macrophages attenuates M1 macrophage polarization and disrupts macrophage-endothelial crosstalk in vitro. cSPECC1 knockdown in macrophages mitigates diabetes-induced retinal inflammation and ameliorates retinal vascular dysfunction. Mechanistically, cSPECC1 regulates GPX2 expression by recruiting eIF4A3, enhancing GPX2 mRNA stability and altering arachidonic acid metabolism. The metabolic intermediate 12-HETE has emerged as a key mediator, regulating both macrophage homeostasis and the crosstalk between macrophages and endothelial cells. Exogenous 12-HETE supplementation interrupts the anti-angiogenic effects of cSPECC1 knockdown. Collectively, circSPECC1 emerges as a novel regulator of macrophage-mediated vascular integrity and inflammation. Targeting the metabolic reprogramming of macrophages presents a promising therapeutic strategy for mitigating diabetes-induced vascular dysfunction.