JAM3 is a junctional adhesion molecule that functions as a heterotypic cell-cell adhesion mediator, serving as a counter-receptor for JAM2 1. It is expressed across multiple tissues including kidney, brain, placenta, and endothelial cells 1, and its expression increases upon lymphocyte activation 1. JAM3 plays a role in hematopoietic stem cell (HSC) migration and mobilization through downstream signaling from mechanical stress sensors, contributing to myeloid differentiation via the PIEZO1-JAM3-CAPN2 pathway 2. As a tumor suppressor, JAM3 is frequently epigenetically silenced in multiple cancers. In serous ovarian carcinoma, JAM3 suppresses proliferation and invasion by inhibiting the PI3K/AKT signaling pathway 3. In esophageal cancer, JAM3 methylation correlates with poor prognosis and promotes tumorigenesis through Wnt/β-catenin pathway activation 4. JAM3 methylation serves as a biomarker for cervical cancer risk stratification, demonstrating superior sensitivity (83.8-91.2%) and specificity (95.3-95.8%) compared to HPV testing alone in identifying cervical intraepithelial neoplasia grade 2+ lesions 567. Mutations in JAM3 are associated with hemorrhagic destruction of the brain with subependymal calcification and cataracts, highlighting its importance in vascular and neural integrity.