Work

B2M regulates ELANE in pyroptosis to affect pancreatic cancer progression

Year: 2025

Type: article

Abstract: • By employing Mendelian Randomization-Mediation Combined Analysis (MR-mediation combined analysis), we unveiled the B2M-ELANE regulatory axis. This was achieved by integrating two-sample Mendelian Randomization (MR) with mediation analysis. Our findings reveal that B2M indirectly influences the risk of pancreatic cancer by modulating ELANE, with a mediation effect accounting for 20.572 %, thereby proposing a novel pathogenic mechanism. • Multi-Database Genetic Evidence Integration. Synthesized GWAS and pQTL data from FinnGen, Icelandic, and UK Biobank cohorts to construct a hierarchical causal inference network. • Single-Cell Microenvironment Validation:Validated B2M's role in tumor immune infiltration using single-cell resolution analysis and UCSC XENA transcriptomic data. • Therapeutic Target Translation:Proposed B2M as a biomarker/therapeutic target via drug sensitivity screening, identifying candidate agents for precision treatment. 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.

Source: Translational Oncology

DOI: 10.1016/j.tranon.2025.102613

Authors: Hui xie, Xiaonan Hu, Yongde Cai, Sheng Zhu, Zuliang Deng

Institutions: Xiangnan University, Macao Polytechnic University

Language: English

Topic: Pancreatic and Hepatic Oncology Research

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,390