PUBLICATION
Erdafitinib suppresses pathological retinal angiogenesis via dual targeting of FGFR and VEGFR2 signaling
- Authors
- Mo, Y., Lu, B., Xu, Y., Fan, X., Zhang, Q., Cheng, S., Tang, L., Peng, Q.
- ID
- ZDB-PUB-251023-7
- Date
- 2025
- Source
- Scientific Reports 15: 3689036890 (Journal)
- Registered Authors
- Keywords
- AKT/ERK signaling, Erdafitinib, Oxygen-induced retinopathy (OIR) model, Retinal angiogenesis, VEGFR2, Zebrafish
- MeSH Terms
-
- Angiogenesis
- Angiogenesis Inhibitors/pharmacology
- Animals
- Cell Movement/drug effects
- Disease Models, Animal
- Human Umbilical Vein Endothelial Cells/drug effects
- Humans
- Mice
- Molecular Docking Simulation
- Neovascularization, Pathologic*/drug therapy
- Pyrazoles*/pharmacology
- Quinoxalines*/pharmacology
- Receptors, Fibroblast Growth Factor*/antagonists & inhibitors
- Receptors, Fibroblast Growth Factor*/metabolism
- Retinal Neovascularization*/drug therapy
- Retinal Neovascularization*/metabolism
- Retinal Neovascularization*/pathology
- Signal Transduction*/drug effects
- Vascular Endothelial Growth Factor Receptor-2*/antagonists & inhibitors
- Vascular Endothelial Growth Factor Receptor-2*/metabolism
- Zebrafish
- PubMed
- 41125751 Full text @ Sci. Rep.
Citation
Mo, Y., Lu, B., Xu, Y., Fan, X., Zhang, Q., Cheng, S., Tang, L., Peng, Q. (2025) Erdafitinib suppresses pathological retinal angiogenesis via dual targeting of FGFR and VEGFR2 signaling. Scientific Reports. 15:3689036890.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping