EFNA1 (ephrin A1) is a GPI-bound cell surface ligand for Eph receptor tyrosine kinases that mediates contact-dependent bidirectional signaling crucial for vascular and developmental processes 12. Physiologically, EFNA1 regulates vascular endothelial cell differentiation and angiogenesis through EPHA2 activation and inhibits epithelial-to-mesenchymal transition in cardiac development 3. In pathological contexts, EFNA1 plays a prominent oncogenic role across multiple cancers. In cervical cancer, tumor-specific super-enhancers drive EFNA1 overexpression via FOSL2-dependent transcription, promoting cell proliferation and migration through EphA2-mediated Src/AKT/STAT3 pathway activation 4. In gastric cancer, EFNA1 signaling upregulates CCL2 secretion via the Hippo-YAP pathway, facilitating hepatic premetastatic niche formation and liver metastasis 5. EFNA1 is identified as a key driver and non-invasive biomarker of ovarian cancer metastasis, with high expression correlating with stem-like tumor cell states and immune evasion 6. Clinically, EFNA1 expression correlates with poor patient outcomes across gastrointestinal and other malignancies 78. Conversely, inhibiting Eph/ephrin signaling with pan-ephrin blockers reduces vascular endothelial dysfunction in sepsis 9. These findings establish EFNA1 as both a prognostic biomarker and potential therapeutic target in cancer and inflammatory diseases.