Background <p>Endometrial cancer (EC) threatens women’s health. The Na⁺/H⁺ Exchanger 7 (NHE7) is implicated in cancer progression, but its role in EC and potential link to endoplasmic reticulum (ER) stress remain poorly understood.</p> Methods <p>NHE7 was overexpressed or knocked down in EC cells. Functional assays and transcriptomic analyses were performed. Supernatant (SN) or exosomes from donor EC cells were applied to recipient cells. Mechanistic studies included exosome inhibition (GW4869), bioinformatic analysis, dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP), and ER stress manipulation (4-PBA/Tunicamycin). In vivo tumor models validated findings.</p> Results <p>NHE7 promoted malignant phenotypes, EMT, and stemness via ER stress activation. SN/exosomes from NHE7-overexpressing cells transmitted these phenotypes and ER stress to recipient cells, which were blocked by GW4869 or 4-PBA. PRSS1 was identified as a key NHE7 downstream target, and its exosomal delivery mediated ER stress transmission. Mechanistically, NHE7 drove PRSS1 transcription in donor cells via ER stress-dependent c-Fos recruitment to the PRSS1 promoter. In recipient cells, PRSS1 upregulated ERP27 to amplify ER stress. TCGA data showed that high PRSS1 expression correlated with poor prognosis. In vivo, NHE7 accelerated tumor growth and upregulated PRSS1/ERP27, effects reversed by 4-PBA.</p> Conclusion <p>NHE7 functions as a key regulator of ER stress signaling transmission in EC cells, driving malignant phenotypes and stemness through the c-Fos/PRSS1/ERP27 axis. Targeting this axis may offer a novel therapeutic strategy for EC.</p> Graphical Abstract <p></p>