B2M regulates ELANE in pyroptosis to affect pancreatic cancer progression.

The role of pyroptosis in pancreatic cancer remains controversial. Using two-sample Mendelian randomization (MR) integrating GWAS data from FinnGen (314,193 controls, 731 cases), pQTL data from Iceland, and the UK Biobank, we systematically investigated causal links between pyroptosis genes and pancreatic cancer. We found that Beta-2-microglobulin (B2M) indirectly increases pancreatic cancer risk by upregulating Neutrophil Elastase (ELANE)-to our knowledge, this is the first study to establish a causal, mediation-based genetic link between B2M and ELANE in the context of pancreatic cancer. Mediation analysis revealed ELANE accounts for 20.572 % [15.32%-25.81 %] of this effect. Sensitivity analyses confirmed robustness without significant pleiotropy, and bioinformatics validation supported our MR findings. Drug sensitivity analysis further identified potential therapeutic agents. The findings support B2M as a diagnostic biomarker for pancreatic cancer, given its significant overexpression in tumors and high diagnostic accuracy (AUC = 0.976, 95 % CI: 0.958-0.993), and highlight the B2M-ELANE axis-identified through a data-driven MR mediation framework-as a promising therapeutic target.