SCUBE2 is a multifunctional secreted and membrane-associated protein with context-dependent roles in development, vascular biology, and disease. Primarily, SCUBE2 mediates Sonic hedgehog (SHH) signaling by binding lipid-modified SHH and promoting its mobilization and proteolytic release from cell membranes, thereby enabling long-range SHH signaling 12. Beyond SHH biology, SCUBE2 serves as a coreceptor for VEGFR2 in vascular endothelial cells, facilitating VEGF-induced angiogenesis through formation of SCUBE2-VEGF-VEGFR2 signaling complexes 3. SCUBE2 additionally stabilizes vascular barrier function by recruiting VE-PTP to dephosphorylate VE-cadherin at adherens junctions, preventing endocytosis and maintaining endothelial integrity 4. Disease relevance is substantial: SCUBE2 expression associates with pulmonary fibrosis pathogenesis through alveolar fibroblast-to-pathological fibroblast transitions 5, promotes bone metastasis in luminal breast cancer via SHH-mediated osteoblastic niche remodeling 6, and increases during atherosclerosis development correlating with vascular inflammation 78. In non-small cell lung cancer, SCUBE2 exhibits tumor-suppressive activity by inhibiting proliferation and migration through SHH pathway suppression 9. Clinically, SCUBE2 shows promise as a prognostic marker in hormone receptor-positive cancers and potential therapeutic target in fibrotic and metastatic diseases.