EFNA4 (ephrin A4) encodes a cell surface GPI-bound ligand that functions in both receptor-dependent and receptor-independent mechanisms. In the canonical pathway, EFNA4 binds to Eph receptors to mediate bidirectional signaling crucial for axon guidance and neural development 1. EFNA4 forms co-receptor complexes with TrkB and mediates reverse signaling required for callosal axon growth toward the midline, with this function dependent on TrkB-SHC signaling 1. Beyond neural development, EFNA4 acts as an oncogene in multiple cancer types through receptor-independent mechanisms. In hepatocellular carcinoma, EFNA4 directly interacts with SLC7A11 and recruits deubiquitinase USP9X, leading to SLC7A11 stabilization and ferroptosis inhibition, thereby promoting tumor proliferation and metastasis 2. In gastric cancer, EFNA4 positively regulates PYGO2 expression and activates Wnt/β-catenin signaling to enhance cell migration, invasion, stemness, and angiogenesis 34. EFNA4 amplification is associated with lung adenocarcinoma lymph node metastasis and poor prognosis 5. Additionally, EFNA4 variants have been linked to craniosynostosis 6, and elevated EFNA4 levels correlate with diabetic neuropathy severity 7, suggesting broader roles in disease pathogenesis.