EFNA3 (ephrin A3) encodes a glycosylphosphatidylinositol-anchored cell surface ligand that binds to EphA receptors, mediating bidirectional signaling crucial for cellular communication and tissue development. In cancer contexts, EFNA3 functions as an oncogene promoting tumor progression through multiple mechanisms. In hepatocellular carcinoma, EFNA3 is upregulated by HIF-1α under hypoxic conditions and activates the EphA2/SREBP1/ACLY metabolic pathway, enhancing cancer stemness and tumor initiation 1. The protein promotes epithelial-to-mesenchymal transition in colorectal cancer through EphA3/EFNA3 reverse signaling and ERK pathway activation, facilitating metastasis 2. EFNA3 expression correlates with poor prognosis in multiple cancers, including breast cancer where hypoxia-induced EFNA3 long noncoding RNAs increase metastatic potential 3. In gastric cancer, EFNA3 is regulated by the LINC01270/miR-326 axis and promotes cell proliferation, migration, and invasion 4. Beyond oncology, EFNA3 serves as a therapeutic target, as artesunate inhibits choroidal melanoma progression by downregulating EFNA3 through Stat3/Akt signaling 5. In cardiovascular biology, EFNA3 is regulated by exercise-induced miR-210, where its downregulation contributes to cardiomyocyte proliferation and cardioprotection against ischemia/reperfusion injury 6. Additionally, embryonic EFNA3 signaling plays a role in endometrial receptivity during implantation 7.