Belzutifan Attenuates Choroidal Neovascularization by Suppressing the HIF ‐2α/ PAI ‐1 Axis

ABSTRACT Choroidal neovascularization (CNV) is the hallmark pathology of exudative age‐related macular degeneration (AMD). Although anti‐vascular endothelial growth factor (VEGF) therapy is widely used, its limitations, including drug resistance and treatment burden, necessitate alternative targets. This study aimed to investigate the role of hypoxia‐inducible factor‐2α (HIF‐2α) in CNV pathogenesis and evaluate the therapeutic potential of its inhibitor Belzutifan, with a particular focus on validating the functional significance of the HIF‐2α/plasminogen activator inhibitor‐1 (PAI‐1) axis. The efficacies of Belzutifan were assessed in a laser‐induced CNV rat model using H&E staining, OCT, fundus photography, and immunofluorescence. Network pharmacology identified potential therapeutic pathways. In vitro, CoCl ₂ ‐injured HUVECs were used to evaluate the effects of drugs on proliferation, migration, and tube formation. The expression levels of HIF‐2α, PAI‐1, VEGF‐A, Ve‐cadherin, and inflammatory factors were assessed by ELISA, immunofluorescence, and Western blot analysis. This study demonstrated that Belzutifan inhibits CNV by targeting the HIF‐2α/PAI‐1 axis. It also showed that Belzutifan can markedly reduce the expression levels of pro‐inflammatory cytokines (IL‐6, IL‐1β, and TNF‐α). Both the HIF‐2α inhibitor and the PAI‐1 inhibitor suppressed the proliferation, migration, and tube formation of HUVECs. Intravitreal injection of both inhibitors effectively reduced neovascularization from Day 14 to Day 21 in the laser‐induced CNV rat model. Collectively, these findings provide a novel therapeutic strategy for exudative AMD and highlight its significant clinical translational value.