Icariin alleviates corneal neovascularization by regulating inflammation through inhibition of macrophage polarization and the NF-κB pathway.

BACKGROUND: Corneal neovascularization (CorNV) is a vision-threatening complication arising from various pathological conditions. While persistent inflammation has been established as the core driver, its underlying mechanisms have not been fully elucidated. Current first-line anti-vascular endothelial growth factor (anti-VEGF) therapies are limited by non-responsiveness and recurrence, often associated with ongoing inflammatory activity. The flavonoid compound icariin (ICA) reportedly exhibits potent anti-inflammatory properties and has been widely used to manage systemic inflammatory conditions. However, its specific role in CorNV has not been fully elucidated. METHODS: This study established two models of corneal neovascularization using alkali burn and suture techniques, followed by treatment with ICA. Next, the area of neovascularization and the degree of corneal inflammatory edema were quantified. Using immunofluorescence, flow cytometry, and ELISA techniques, the expression levels of M1 macrophage markers, proinflammatory cytokines (IL-1β, IL-6, TNF-α), and VEGF were assessed both in vivo (following corneal injury) and in vitro (in RAW264.7 macrophages). NF-κB pathway activity was assessed using western blot and immunofluorescence techniques. RESULTS: ICA significantly reduced the area of CorNV and attenuated inflammatory cell infiltration. These effects were associated with down-regulation of M1 macrophage markers in both corneal tissue and cultured macrophages. Mechanistically, ICA inhibited phosphorylation of IκBα and NF-κB, thereby reducing NF-κB translocation to the nucleus and reducing expression levels of IL-1β, IL-6, TNF-α, and VEGF. CONCLUSION: Our study findings suggest that by inhibiting NF-κB signaling and M1 macrophage polarization, ICA effectively mitigates CorNV, offering a novel therapeutic strategy for this patient population. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-07813-y.