EPHA4

Ephrin type-A receptor 4 (EPHA4), a member of the Eph receptor tyrosine kinase family, mediates cell-cell communication through binding to membrane-anchored ephrin ligands. Also known as HEK8 or TYRO1, it regulates bidirectional signaling pathways influencing cell adhesion, migration, and axon guidance during neurodevelopment. EPHA4 modulates Rho GTPase and MAPK/ERK cascades to orchestrate cytoskeletal dynamics and tissue patterning. Dysregulation of EPHA4 is implicated in amyotrophic lateral sclerosis (ALS), where reduced expression correlates with motor neuron degeneration, and in cancers such as glioblastoma through pro-invasive signaling. Preclinical studies highlight its dual role in spinal cord injury—promoting axonal regeneration yet inhibiting functional recovery via glial scar formation. While no EPHA4-targeted therapies are clinically approved, small-molecule inhibitors (e.g., dasatinib repurposing) and monoclonal antibodies are under investigation for neurological and oncological applications, though challenges persist in balancing its context-dependent pro-regenerative and pathological activities.