EYA4 is a multifunctional tyrosine phosphatase that regulates DNA repair, transcription, and cell cycle progression. Its primary catalytic function involves dephosphorylating histone H2AX at tyrosine 142, promoting efficient DNA repair and distinguishing between apoptotic and repair responses to genotoxic stress 1. Beyond DNA repair, EYA4 dephosphorylates PLK1 at tyrosine 445 during G2 phase, enabling centrosome maturation and successful mitosis 2. EYA4 also regulates transcription factors; it dephosphorylates β-catenin and SIX1, inhibiting their tumor-promoting activities 34. Additionally, EYA4 functions as a component of μ-opioid receptor signaling networks 5. EYA4 exhibits tissue-dependent tumor roles: it acts as a tumor suppressor in non-nervous system cancers including intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma 63, but promotes tumor growth in nervous system malignancies 1. Clinically, reduced EYA4 expression correlates with poor prognosis and shorter survival 634. Mutations cause autosomal dominant deafness (DFNA10) and dilated cardiomyopathy, accounting for 2.5% of genetic non-syndromic hearing loss cases in Europe 7. EYA4 expression in peripheral blood mononuclear cells serves as a biomarker for esophageal carcinogenesis progression 8. EYA4 expression levels and methylation profiles may predict cancer prognosis and treatment response, positioning EYA4 as a potential therapeutic target 1.