EYA4 is a tyrosine phosphatase that dephosphorylates histone H2AX at tyrosine 142, promoting efficient DNA repair and regulating the balance between apoptotic and repair responses to genotoxic stress. Beyond its role in DNA repair, EYA4 functions as a transcriptional coactivator involved in organogenesis, particularly in eye and ear development. EYA4 interacts with multiple signaling pathways to regulate cell proliferation and survival. Recent studies demonstrate that EYA4 dephosphorylates polo-like kinase 1 (PLK1) at tyrosine 445, a critical modification required for centrosome maturation and successful mitosis 1. EYA4 also dephosphorylates β-catenin in pancreatic cancer, blocking its nuclear translocation and suppressing the β-catenin/ID2 pathway 2. Additionally, EYA4 regulates glucose metabolism reprogramming by dephosphorylating sine oculis homeobox 1 (SIX1) in liver cancer 3. Clinically, EYA4 mutations cause autosomal dominant nonsyndromic hearing loss and cardiomyopathy. In most solid tumors—including intrahepatic cholangiocarcinoma, pancreatic ductal adenocarcinoma, and esophageal cancer—EYA4 acts as a tumor suppressor; reduced expression correlates with worse prognosis and shorter survival [PMID:27469137; 2; 48]. Conversely, EYA4 promotes nervous system malignancies including glioma and peripheral nerve sheath tumors 5. EYA4 expression level and methylation status serve as independent prognostic biomarkers across multiple cancer types, suggesting potential for therapeutic targeting of EYA4 activity.