EPHA8 is a receptor tyrosine kinase that binds ephrin-A ligands to mediate bidirectional cell-cell signaling, with established roles in development and cancer progression. The receptor undergoes clathrin-mediated endocytosis upon ephrin-A5 binding, a process regulated by Tiam-1, a Rac-specific guanine nucleotide exchange factor 1. EPHA8 interacts with SASH1 through SAM-SAM domain interactions, which regulates its kinase activity 2. In cancer contexts, EPHA8 functions as an oncogene across multiple tumor types. It is significantly upregulated in epithelial ovarian cancer, gastric cancer, oral tongue squamous cell carcinoma, and breast cancer, correlating with advanced disease stages, metastasis, and poor prognosis 3456. EPHA8 promotes cancer cell proliferation, migration, and invasion through multiple mechanisms, including regulation of ADAM10 in gastric cancer 4 and AKT signaling pathway activation in breast cancer, where it inhibits apoptosis by modulating Bcl-2, p53, and caspase-3 expression 6. The receptor also regulates epithelial-mesenchymal transition and is negatively regulated by miR-10a in glioma 7. Interestingly, while EPHA8 acts oncogenically in most cancers, it shows downregulated expression in colon cancer and glioblastomas 8.