Knockdown of lipocalin 2 alleviates ocular angiogenesis in diabetic retinopathy by lowering endothelial cell energy metabolism

Abstract Diabetic retinopathy (DR) is increasingly recognized as a neurovascular degenerative disease characterized by early neuronal dysfunction, chronic metabolic stress, and progressive microvascular abnormalities. Clinical studies have reported elevated levels of lipocalin-2 (LCN2) in patients with DR, however, the functional role of LCN2 in diabetic retinal vascular pathology remains poorly defined. In this study, we investigated the contribution of LCN2 to retinal vascular dysfunction under pathological conditions relevant to DR. Using an LCN2 overexpressing mouse model ( LCN2-Tg ) and an endothelium-specific LCN2 knockout mouse model ( Lcn2 fl/fl ; Cdh5-Cre ERT2 ), we examined the effects of LCN2 on retinal vascular remodeling and endothelial function. Our results showed that LCN2 deficiency suppressed both physiological and pathological retinal vascular expansion while preserving vascular stability. Mechanically, LCN2 overexpression was associated with enhanced endothelial cell energy metabolism and exacerbated pathological neovascularization, whereas downregulation of LCN2 suppressed endothelial cell proliferation and migration with restricted metabolic capacity. Collectively, our findings identify LCN2 as a regulator of endothelial metabolic competence in the diabetic retina and suggest that pathological upregulation of LCN2 contributes to retinal microvascular dysfunction. Targeting LCN2-dependent metabolic regulation may therefore represent a potential therapeutic strategy for diabetic retinopathy.