VASN (vasorin) is a secreted glycoprotein that functions as a multifaceted regulator of cell signaling with context-dependent effects on vascular and tumor biology. Mechanistically, VASN acts as a ligand that interacts with Notch1 through its EGF-like domain to modulate Notch signaling 1. In the endothelial KLF15/VASN axis, VASN suppresses angiogenesis by activating Notch1 signaling, providing a negative feedback mechanism for vascular growth 1. Conversely, in cancer contexts, VASN functions as an oncogenic driver. In glioma, low levels of TNFα-mediated VASN promote glioma stem cell self-renewal through enhanced glycolysis 2. In colorectal cancer, VASN activates the YAP/TAZ and PI3K/AKT pathways through YAP interaction, promoting proliferation and EMT 3. In rectal cancer, VASN overexpression correlates with pulmonary metastasis and chemotherapy resistance via Notch1/MAPK pathway activation 4. In gastric cancer, VASN drives tumorigenesis via the COL4A1/PI3K/AKT axis following H. pylori infection 5. Clinically, reduced extracellular vesicle-associated VASN in severe preeclampsia impairs endothelial function and angiogenesis, suggesting VASN serves protective roles in normal pregnancy 6. VASN thus represents a therapeutic target across multiple pathologies including impaired angiogenesis, cancer progression, and vascular dysfunction.