EPHB3 is a receptor tyrosine kinase mediating bidirectional signaling through transmembrane ephrin-B ligands, functioning as a key regulator of developmental processes and tissue homeostasis. Primary functions include axon guidance, dendritic spine development, angiogenesis, and intestinal epithelium differentiation 1. In the intestinal epithelium, EPHB3 regulates Paneth cell localization and crypt symmetry during regeneration, with WNT4 promoting symmetric fission through EphB3-mediated positioning 2. Mechanistically, EPHB3 controls cell-cell adhesion and intercellular communication. In CNS inflammation, microglia-expressed ephrin-B3 signals through EphB3 on astrocytes to promote proinflammatory responses in experimental autoimmune encephalomyelitis, with CNS-penetrant EphB3 inhibitors suppressing these pathological interactions 3. In fibrosis, soluble ephrin-B2 generated by ADAM10 shedding activates fibroblasts via EphB3 signaling, promoting myofibroblast activation and organ fibrosis 4. Clinical significance: EPHB3 functions as a tumor suppressor in colorectal cancer through transcriptional enhancer regulation involving Wnt/β-catenin and Notch signaling; enhancer decommissioning causes EPHB3 silencing at the adenoma-carcinoma transition 1. Elevated EphB3 expression serves as a biomarker in 37% of colorectal cancer samples, with diagnostic potential alongside miR-3168 in serum exosomes 5. Additionally, EPHB3 participates in ferroptosis-related preeclampsia pathogenesis through ARID3A regulation 6.