SCUBE3 is a secreted multifunctional glycoprotein that functions as a critical positive regulator of skeletal development and tissue regeneration. Mechanistically, SCUBE3 acts as a BMP2/BMP4 co-receptor that recruits BMP receptor complexes into lipid raft microdomains, facilitating interactions between BMPs and BMP type I receptors to enhance signaling 1. It also binds to TGFBR2 and activates TGF-β signaling 2. During osteogenic differentiation, SCUBE3 levels increase significantly and promote osteogenesis through BMP2/TGF-β pathway activation and mitophagy induction 3. In dental development, epithelium-derived SCUBE3 translocates paracrine to mesenchymal cells where it enhances odontoblastic differentiation and pulp regeneration 2. Hair follicle development also depends on SCUBE3 secretion by dermal papilla fibroblasts; microinjection of SCUBE3 protein alone is sufficient to induce new hair growth 4. Biallelic SCUBE3 inactivation causes a syndromic disorder with short stature, skeletal anomalies, craniofacial dysmorphism, and dental defects 1. Clinically, SCUBE3 is pathologically elevated in multiple cancers where it promotes tumor progression through EGFR and TGFβRI/II interactions, supporting oncogenic signaling, therapy resistance, and immunosuppression 567. High SCUBE3 expression correlates with poor prognosis in osteosarcoma and ovarian cancer patients 86.