EYA3 is a multifunctional tyrosine phosphatase and transcriptional coactivator with roles in DNA repair, transcriptional regulation, and disease pathogenesis. Biochemically, EYA3 functions as a tyrosine phosphatase that specifically dephosphorylates H2AX at Tyr-142, promoting efficient DNA repair and recruitment of repair complexes 1. Additionally, EYA3 recruits PP2A-B55α to dephosphorylate Myc at Thr-58, stabilizing Myc and enhancing cell proliferation 23. EYA3 serves as a transcriptional coactivator of SIX family proteins, with its activity regulated by alternative splicing during myogenesis through RBFOX2-mediated control 4. EYA3 identifies WDR1 as a tyrosine phosphatase substrate, regulating actin cytoskeletal reorganization 5. Disease relevance is substantial: EYA3 promotes triple-negative breast cancer progression by stabilizing Myc and suppressing NK cell infiltration into the premetastatic niche via NF-κB/CCL2 signaling 6. In Ewing sarcoma, EYA3 promotes tumor growth and angiogenesis through VEGFA regulation and DNA damage repair 1. EYA3 elevation in pulmonary arterial hypertension promotes vascular remodeling by enhancing smooth muscle cell survival under DNA damage 7. Therapeutically, EYA3 tyrosine phosphatase inhibition represents a viable strategy across multiple cancer types and pulmonary hypertension.