ROBO4 is an endothelial-specific transmembrane receptor that functions as a key mediator of vascular development and homeostasis 1. As a receptor for Slit proteins, particularly SLIT2, ROBO4 regulates endothelial cell migration, proliferation, and angiogenesis while maintaining vascular integrity and barrier function 21. ROBO4 expression is controlled by transcription factors (SP1, ETV2) and epigenetically regulated through DNA methylation and TET2-mediated demethylation 34. Clinically, ROBO4 variants are associated with bicuspid aortic valve and thoracic aortic aneurysm, where impaired ROBO4 function causes endothelial barrier dysfunction and endothelial-to-mesenchymal transition 2. ROBO4 dysfunction also contributes to septic shock pathology through increased vascular permeability 5. In diabetic retinopathy, TET2-mediated ROBO4 hypomethylation increases ROBO4 expression, promoting retinal vascular leakage and neovascularization 6. Conversely, in bladder cancer, miR-204 suppresses ROBO4 to inhibit cell growth and metastasis, suggesting context-dependent roles in pathological angiogenesis 7. ROBO4 represents a promising therapeutic target for treating both developmental angiogenesis defects and pathological conditions including ocular neovascularization and tumors 1.