Abstract

Background Pancreatic adenocarcinoma (PAAD) is a highly lethal digestive system tumor with a low five-year survival rate and limited treatment efficacy, underscoring the need for new therapeutic targets. Disulfidptosis, a novel cell death mechanism, shows promise for tumor therapy. Glucose-6-phosphate dehydrogenase (G6PD), a key gene in disulfidptosis, regulates antioxidant defense, biosynthesis, and metabolism. This study investigates G6PD’s role in PAAD and its therapeutic potential via bioinformatics and in vitro experiments. Methods We analyzed the expression of G6PD in PAAD and its correlation with clinical characteristics using data matrices from multiple public databases. At the same time, we evaluated the correlation of G6PD expression with the immune microenvironment and immunotherapy. Finally, GO/KEGG enrichment analysis identified the biological processes related to G6PD, and in vitro experiments preliminarily identified the potential of G6PD as an activation target for disulfidptosis in PAAD. Results G6PD is overexpressed in PAAD and correlates with clinical stage, histological grade, and prognosis. It shows positive associations with immune cell types, regulatory genes, MHC molecules, and chemokines, suggesting that G6PD expression was associated with immune cell infiltration scores and immunomodulatory signatures in PAAD. GO/KEGG analysis linked G6PD to the pentose phosphate pathway, glutathione, and NADPH metabolism, highlighting its role in redox homeostasis and metabolic reprogramming. The G6PD inhibitor RRx-001 induces disulfidptosis-like features in the PAAD cell line SW1990 by reducing NADPH generation, suppressing cystine uptake, and promoting F-actin contraction and aggregation. Conclusions Our study reveals the critical role of G6PD in PAAD. High G6PD expression is closely associated with unfavorable clinicopathological features and poor prognosis in PAAD patients, as well as with specific tumor immune microenvironment characteristics. The G6