Promoter Hypermethylation‐Induced Silencing of FXYD1 Drives Breast Cancer Metastasis via DDX5‐Mediated Wnt/β‐Catenin Pathway Activation

ABSTRACT Epigenetic silencing of tumor suppressor genes is a hallmark of cancer progression. The FXYD (FXYD domain‐containing ion transport regulator) family, classically known for ion transport regulation, has recently been implicated in oncogenesis; however, the role of its founding member, FXYD1, in breast cancer remains unclear. Here, FXYD1 is identified as a significantly downregulated gene in breast cancer tissues, and low FXYD1 expression is associated with unfavorable patient prognosis. Integrative transcriptomic, clinical, and epigenetic analyses revealed that promoter hypermethylation drives FXYD1 silencing. Functional restoration of FXYD1 suppressed cell proliferation, migration, and lung metastasis both in vitro and in vivo. Mechanistically, FXYD1 acts as a nuclear scaffold that recruits the E3 ubiquitin ligase MAEA to the RNA helicase DDX5, a coactivator of β‐catenin, promoting K63‐linked ubiquitination and proteasomal degradation of DDX5. This process reduces β‐catenin stability, impairs its nuclear translocation, and attenuates Wnt target gene expression. Collectively, our findings uncover a previously unrecognized FXYD1–MAEA–DDX5 axis that inhibits Wnt/β‐catenin signaling through a non‐canonical ubiquitin–proteasome pathway, establishing FXYD1 as a tumor suppressor and potential prognostic biomarker and therapeutic target in breast cancer.