NHE7 drives endometrial cancer progression by delaying senescence through cAMP/CREB/GRIN2B axis-mediated Ca²⁺ influx.

Endometrial cancer (EC) remains a lethal gynecological malignancy with limited therapeutic options owing to unresolved pathogenesis. Cellular senescence acts as a key barrier against tumorigenesis in cancer cells, thus investigating its role in EC progression represents a pivotal research avenue to address these challenges. This study reveals the critical role of cellular senescence in EC progression through multi-omics profiling and functional validation. The integrative analysis of RNA-seq and clinical datasets identified Na/H exchanger 7 (NHE7) as a prognostic biomarker that was significantly overexpressed in EC tissues. Functional studies demonstrated that NHE7 overexpression drives proliferation, cell motility, and cell cycle progression while suppressing senescence-associated markers and cytokine secretion. Conversely, NHE7 knockdown reversed these oncogenic phenotypes. Mechanistically, NHE7 binds to a cAMP-related transcription factor, thereby increasing GRIN2B expression to elevate intracellular Ca²⁺ levels influx, which delays cell senescence and promotes cancer progression in vitro and in vivo. Our findings suggest that NHE7 plays a crucial role in delaying cellular senescence and advancing EC progression through the cAMP pathway, uncovering critical mechanistic drivers of EC pathogenesis and highlighting actionable therapeutic targets.