Abstract
Background: Endometrial Cancer (EC) is one of the most prevalent malignancies in the female reproductive system. Hypoxia is a hallmark of the tumor microenvironment that drives metabolic reprogramming, endoplasmic reticulum (ER) stress, and aggressive behavior in cancer cells. However, the underlying mechanisms remain incompletely understood. This study aimed to investigate hypoxia-mediated regulation of EC progression, focusing on the role of SLC9A7 (Solute Carrier Family 9 Member A7, NHE7). Methods: EC cells were exposed to hypoxic conditions (1% O2) to assess phenotypic changes. Transcriptomic analysis, RT-qPCR, and western blotting were utilized to identify hypoxia-induced targets. Functional assays (proliferation, migration, invasion, tumor spheroid formation) and a xenograft mouse model were performed to evaluate NHE7's roles. Bioinformatics analysis, pharmacological interventions (4-PBA, Ceapin-A7, 2-DG, Sodium oxamate), and chromatin immunoprecipitation (ChIP) were used to dissect molecular mechanisms. Results: Hypoxia promoted the malignant phenotypes and stemness of EC cells. NHE7 was identified as a potential target gene of the hypoxia pathway and was positively correlated with poor prognosis in EC. Furthermore, overexpression of NHE7 in xenografts accelerated tumor growth. Mechanistically, NHE7 enhanced oxidative phosphorylation (OXPHOS) by elevating COX6C (Cytochrome C Oxidase Subunit 6C) expression, further driving ER stress. Hypoxia-driven glycolysis elevated histone lactylation, which transcriptionally activated NHE7. This regulation was reversed by glycolysis or lactate production inhibitors. Conclusion: Hypoxia-driven glycolysis induces histone lactylation, leading to the upregulation of NHE7 expression. This process enhances OXPHOS-induced ER stress by upregulating COX6C expression, ultimately contributing to the malignant progression of EC.