EFNB1 (ephrin B1) is a cell surface transmembrane ligand for Eph receptor tyrosine kinases that mediates contact-dependent bidirectional signaling crucial for developmental processes 1. Beyond its classical role in neuronal development, EFNB1 has emerged as a significant player in pathological contexts. In cancer, tumor cells release EFNB1-containing exosomes that promote axonogenesis and tumor innervation, which correlates with poor prognosis and increased metastasis 23. In esophageal squamous-cell carcinoma, aberrant EFNB1-EPHB4 interaction within epithelial cells triggers epithelial-mesenchymal transition and proliferation through SRC/ERK/AKT signaling, driven by TP53 mutation-induced ΔNP63 overexpression 4. EFNB1 also mediates tumor-platelet crosstalk in pancreatic cancer liver metastasis via reverse signaling, promoting metastatic outgrowth through platelet activation and serotonin release 5. In inflammatory disease, T cell-expressed EFNB1 is essential for pathogenic antibody production and T cell migration in rheumatoid arthritis, with elevated EFNB1 correlating with disease activity 6. Additionally, senescent cells express elevated EFNB1 as part of their pro-survival network, making it a therapeutic target for senolytic drugs 7. These findings reveal EFNB1's multifaceted roles beyond development in cancer progression, inflammation, and aging.