Abstract
BACKGROUND: Gastric cancer (GC) has a poor prognosis, and its pathogenesis remains incompletely understood. Endoplasmic reticulum stress (ERS) may influence GC progression, yet ERS-based prognostic models are lacking. We aimed to develop an ERS-related prognostic signature using single-cell analysis and identify potential therapeutic targets. METHODS: Integrated analyses including single-cell RNA sequencing, cell‒cell communication, GSVA enrichment, and drug sensitivity inference were performed. A 14-gene prognostic model was constructed using Cox regression and LASSO, and validated via Kaplan-Meier and ROC curves. NOX5 function was assessed through in vitro proliferation and migration assays. RESULTS: The ERS signature outperformed clinicopathological parameters in predicting GC survival, with AUCs of 0.75, 0.71, and 0.64 for 1-, 3-, and 5-year OS, respectively. Patients were stratified into high- and low-risk groups with distinct immune checkpoint profiles. NOX5, the top risk gene (HR > 2.0), was upregulated in GC, and its knockdown significantly suppressed AGS and MKN-45 cell proliferation and migration (p < 0.01). CONCLUSION: The ERS-related signature is a promising independent prognostic and predictive biomarker for GC. NOX5 represents a novel potential therapeutic target.