biostudies-literatureUnknown63Xie HHunan Provincial Natural Science FoundationEducation Department of Hunan ProvinceThe 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 Translational oncology102613https://www.ebi.ac.uk/biostudies/studies/S-EPMC12681877biostudies-literatureB2M regulates ELANE in pyroptosis to affect pancreatic cancer progression.PMC12681877Xie HHu XDeng ZCai YZhu SfalseB2M 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 2025-01-01T00:00:00Z2025 Nov2026-06-05T23:37:57.448Z2026-05-23T03:13:53.921ZS-EPMC126818774127398910.1016/j.tranon.2025.102613