Decoding the diabetes-pancreatic adenocarcinoma connection: the critical role of PILRA in intermediate monocyte activity.

Diabetes is a well-known risk factor for pancreatic adenocarcinoma (PAAD), yet the underlying molecular mechanisms remain unclear. This study employs single-cell sequencing to analyze gene expression patterns and uses Mendelian randomization to assess the association between genetic variations in specific genes and the risk of PAAD. Our findings reveal a significant reduction in the proportion of monocytes in patients with both diabetes and PAAD. Monocytes play a crucial role in the progression of both diseases. Notably, we identified an increase in intermediate monocytes (CD14 + + CD16+) in both conditions. These cells exhibit significant activation of the LGALS9-CD45 receptor, increased metabolic activity, and enhanced involvement in disease pathways. We demonstrate that intermediate monocytes are key cellular players in the link between diabetes and PAAD. Using dual-sample Mendelian randomization, we identified genetic variations in PILRA, a highly variable gene in intermediate monocytes, as a risk factor for PAAD. PILRA + intermediate monocytes show higher metabolic activity and stronger immune cell communication compared to PILRA- cells, suggesting an important role in tumor microenvironment regulation and immune cell activation inhibition. This biological function is associated with cytokine-mediated signaling, focal adhesion, and NOD-like receptor signaling pathways. RT-qPCR validation of PBMC samples indicates a statistically significant, progressive increase in PILRA expression in patients with PAAD, diabetes, and those with both conditions. In summary, this study uncovers the critical role of intermediate monocytes in diabetes-induced PAAD and proposes PILRA as a potential therapeutic target.