EPHA4 (EPH receptor A4) is a receptor tyrosine kinase that binds membrane-bound ephrin ligands to mediate contact-dependent bidirectional signaling between adjacent cells 1. Uniquely promiscuous among Eph receptors, EPHA4 activates both GPI-anchored ephrin-A and transmembrane ephrin-B ligands, regulating cell morphology and adhesion through Rac, Rap, and Rho GTPase signaling. During nervous system development, EPHA4 controls axonal guidance and corticospinal projection establishment while regulating synaptic plasticity and dendritic spine morphogenesis 2. However, EPHA4 also inhibits axonal regeneration after injury, positioning it as a potential therapeutic target for promoting neuroregeneration 3. Pathologically, elevated EPHA4 expression correlates with multiple neuropsychiatric and neurodegenerative conditions. In major depressive disorder, EPHA4 upregulation in excitatory neurons drives demyelination and depression-like behaviors, with EphA4 inhibition preventing both phenotypes 4. In Alzheimer's disease, astrocytic EphA4 signaling mediates excitatory synapse elimination through complement-dependent mechanisms; astrocyte-specific EphA4 knockout ameliorates hippocampal synapse loss and cognitive decline 5. EPHA4 also promotes amyloid-β oligomer-induced synaptotoxicity via c-Abl activation 2. Additionally, EphA4 inhibition reduces vascular leak and endothelial dysfunction in sepsis 6, and EPHA4 is implicated in retinal neovascularization pathways 7. EPHA4/EPHA2 inhibitors show therapeutic potential in endometriosis and cancer 8.