<i>NOX4</i> Shapes Inflammatory Microenvironment and Predicts Prognosis and Therapeutic Response in Gastric Cancer

<h3>Abstract</h3> <h3>Background/Aim:</h3> 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. <h3>Materials and Methods:</h3> 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, <i>NOX4</i>, were comprehensively evaluated using TCGA clinical data and diverse bioinformatics platforms. <h3>Results:</h3> <i>NOX4</i> was identified as a significantly overexpressed inflammation-related hub gene in STAD, correlating with <i>Helicobacter pylori</i> infection and advanced pathological staging. High <i>NOX4</i> expression predicted a poor prognosis. A nomogram integrating <i>NOX4</i> 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 <i>NOX4</i>’s involvement in pathways such as cytoskeletal organization and ECM-receptor interactions. Immunologically, high <i>NOX4</i> 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 (<i>e.g., TP53, TTN</i>) associated with <i>NOX4</i> levels. Furthermore, drug sensitivity analysis indicated that high <i>NOX4</i> expression was linked to higher IC₅₀ values for 14 chemotherapeutic agents, including cisplatin and sorafenib, indicating potential chemoresistance. <h3>Conclusion:</h3> <i>NOX4</i> 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.