Abstract
Pathological retinal angiogenesis drives vision loss in diseases like proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO). Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor, has shown therapeutic potential in FGFR-mutated urothelial carcinoma. This study aimed to determine whether erdafitinib suppresses pathological retinal angiogenesis beyond its canonical FGFR inhibition, and to dissect its potential mechanisms through multi-model validation. We employed zebrafish developmental angiogenesis and oxygen-induced retinopathy (OIR) mouse models, combined with in vitro endothelial cell assays. In zebrafish, erdafitinib dose-dependently inhibited intersegmental vessel (ISV) formation and disrupted retinal angiogenesis, with confocal microscopy revealing truncated vascular length (by 62% at 4 µM vs. controls). The OIR model demonstrated erdafitinib's efficacy in reducing neovascular density (35% decrease) and pathological tuft formation. Mechanistically, erdafitinib impaired human umbilical vein endothelial cell (HUVEC) tube formation and migration, accompanied by downregulation of VEGFR2 expression (2.1-fold reduction) and inhibition of AKT/ERK phosphorylation. Molecular docking confirmed erdafitinib's binding to VEGFR2 kinase domain (binding energy: -7.8 kcal/mol), albeit with lower affinity than FGFR1 (-10.2 kcal/mol). These findings establish that erdafitinib exerts off-target anti-angiogenic effects by blocking VEGFR2 phosphorylation and downstream signaling, supporting its repurposing potential for anti-VEGF-resistant retinal vascular diseases. Further studies should address its intraocular pharmacokinetics and long-term safety.
Keywords:
AKT/ERK signaling; Erdafitinib; Oxygen-induced retinopathy (OIR) model; Retinal angiogenesis; VEGFR2; Zebrafish.