EPHB2 is a receptor tyrosine kinase that mediates cell-cell communication through binding to membrane-bound ephrin ligands, particularly EFNB1 and EFNB2, enabling bidirectional signaling between adjacent cells 12. In the nervous system, EPHB2 plays crucial roles in axon guidance during development and peripheral nerve regeneration, where it interacts with cleaved ephrin-B2 from fibroblasts to activate Schwann cells and promote axonal repair 2. The receptor regulates autophagy in colonic epithelial cells through ubiquitination by RNF186, which is essential for maintaining intestinal homeostasis 1. In cancer contexts, EPHB2 exhibits dual functions: it acts as a tumor suppressor in colorectal serrated adenocarcinomas where it is downregulated 3, but paradoxically promotes cancer stem cell properties and sorafenib resistance in hepatocellular carcinoma through activation of β-catenin signaling 4. EPHB2 also contributes to NASH progression in liver disease, where EphB2-expressing hepatocytes drive inflammation and fibrosis 5. Additionally, EPHB2 shows prognostic value in breast cancer, with higher expression associated with better treatment response but complex associations with metastasis depending on cancer subtype 6. The receptor's involvement in obesity-related depression through gut-brain axis signaling further demonstrates its diverse physiological roles 7.