New Potential Metabolic Biomarker and Its Role in PDAC: Insights from Genome-Wide Association Studies and Single-cell Analysis

Background Pancreatic ductal adenocarcinoma (PDAC), a perilous malignancy, possesses a complex and largely nebulous etiology, prompting an urgent call to elucidate its underlying mechanisms and define reliable early detection biomarkers. Objective To pinpoint metabolic biomarkers causally linked to PDAC and exploring potential mechanisms. Methods We employed a two-sample mendelian randomization study to identify significant serum metabolites associated with PDAC and conducted single-cell analysis on peripheral blood from PDAC patients and healthy individuals. We also developed a predictive model integrating identified metabolic biomarkers and relevant genes using machine learning techniques. Results We discerned 79 serum metabolites, notably, indole-3-carboxylate levels were found to trigger PDAC onset by down-regulating the protective factor SULT1A1. Single-cell analysis unveiled distinct cellular compositions between PDAC patients and healthy individuals. Given indole-3-carboxylate's interaction with the Aryl hydrocarbon receptor, monocytes were identified as the most affected cell type. A robust correlation was observed between Neutrophils and low receptor monocytes across various pathways, particularly the SELPLG and SEM4 pathways. A PDAC predictive model was developed, with PADI4 and S100P as significant contributors, exhibiting high diagnostic potential. Conclusion Our findings underscore indole-3-carboxylate's potential in triggering PDAC via its interaction with monocyte-associated SULT1A1 and the contributions of PADI4 and S100P. This predictive model for PDAC could pave the way for advancements in early detection and personalized treatment strategies for this lethal disease.