NOX4 Shapes Inflammatory Microenvironment and Predicts Prognosis and Therapeutic Response in Gastric Cancer

The inflammatory microenvironment plays a critical role in stomach adenocarcinoma (STAD); however, the clinical relevance of inflammation-related genes remains unclear. This study aimed to identify key inflammation-related hub genes and evaluate their prognostic, immunological, and therapeutic significance in STAD.

This study integrated six transcriptomic datasets from GEO and TCGA databases to identify differentially expressed genes (DEGs) between STAD and normal tissues. Inflammation-related DEGs were enriched using the MSigDB hallmark gene set, followed by protein-protein interaction (PPI) network analysis to identify hub genes. The expression, diagnostic value, prognostic significance, immune microenvironment associations, and drug sensitivity of the key hub gene, NOX4, were comprehensively evaluated using TCGA clinical data and diverse bioinformatics platforms.

NOX4 was identified as a significantly overexpressed inflammation-related hub gene in STAD, correlating with Helicobacter pylori infection and advanced pathological staging. High NOX4 expression predicted a poor prognosis. A nomogram integrating NOX4 expression, age, and T stage achieved AUC values of 0.730, 0.719, and 0.706 for 1-, 3-, and 5-year overall survival, respectively. Functional enrichment revealed NOX4's involvement in pathways such as cytoskeletal organization and ECM-receptor interactions. Immunologically, high NOX4 expression correlated with increased M2 macrophage infiltration, decreased memory B cells and resting CD4+ memory T cells, and higher TIDE scores, suggesting potential immunotherapy resistance. Mutation analysis showed distinct high-frequency mutations (e.g., TP53, TTN) associated with NOX4 levels. Furthermore, drug sensitivity analysis indicated that high NOX4 expression was linked to higher IC₅₀ values for 14 chemotherapeutic agents, including cisplatin and sorafenib, indicating potential chemoresistance.

NOX4 emerges as a key regulator of the STAD inflammatory microenvironment and a robust prognostic biomarker. Its role in immune modulation and chemoresistance provides novel insights for developing precision therapeutic strategies in STAD.