EFNA5 (ephrin A5) is a cell surface GPI-bound ligand that binds to Eph receptor tyrosine kinases to mediate bidirectional signaling crucial for cellular processes including migration, adhesion, and development 1. The protein functions in multiple biological contexts: it regulates axon guidance and neuronal development, with disruptions linked to neurodevelopmental disorders 2, and plays roles in retinal neovascularization through Efna5-Epha4 signaling pathways 3. In cancer biology, EFNA5 exhibits context-dependent effects - it can act as a tumor suppressor in colorectal cancer where miR-645 targets EFNA5 to promote invasion and metastasis 4, while in pancreatic cancer, EFNA5 accumulation facilitates cancer development when piR-017061-mediated degradation is lost 5. EFNA5 also contributes to cancer microenvironment remodeling, as neoadjuvant therapy reduces EFNA5 expression in cancer-associated fibroblasts, leading to altered collagen architecture in pancreatic cancer tissues 6. Additionally, genetic variations in EFNA5 may contribute to age-related cataract susceptibility in Chinese populations 7. The protein's diverse roles span from normal development to pathological processes, making it both a potential therapeutic target and biomarker across multiple diseases.