PLCG1 regulates pyroptosis to inhibit the progression of non-small cell lung cancer: A Mendelian randomization study.

Authors

Yihui Zhang, Guihui Wang, Ziwen Qin, Ziyan Mo, Jixian Liu

Published in

Medicine. Volume 105. Issue 42. Pages e50908. Oct 16, 2026.

Abstract

Pyroptosis, an inflammatory form of programmed cell death, has been implicated in non-small cell lung cancer (NSCLC) progression. However, the specific pyroptosis-related genes causally linked to NSCLC and their upstream regulatory mechanisms remain poorly understood. We performed a two-sample Mendelian randomization (MR) study to assess causal relationships between 33 pyroptosis-related genes and NSCLC risk using genetic instruments from the deCODE database and outcome data from the FinnGen consortium (6446 NSCLC cases, 378,749 controls). Inverse-variance weighting was the primary analysis method, with MR-Egger, weighted median, and MR-PRESSO as sensitivity analyses. To identify upstream regulators, we integrated pQTL data from the The UK Biobank Pharma Proteomics Project and performed two-step MR mediation analysis. Identified genes were further validated using mRNA expression data from The Cancer Genome Atlas (TCGA) and genotype-tissue expression (GTEx) databases. MR analysis identified 2 pyroptosis-related genes significantly associated with NSCLC: IL1B (odds ratio [OR] = 1.087, 95% confidence interval [CI] = 1.009-1.171, P = .028) and PLCG1 (OR = 0.874, 95% CI = 0.766-0.997, P = .044). Upstream analysis revealed that AMBP and CCNE1 were causally associated with PLCG1 expression. Mediation analysis demonstrated that PLCG1 mediated 11.7% of the total effect of AMBP on NSCLC risk (mediation effect: OR = 1.02, 95% CI = 1.01-1.03, P = .008). mRNA expression validation confirmed that AMBP and PLCG1 were significantly upregulated in NSCLC tissues compared to normal tissues (P < .001). This study establishes causal links between pyroptosis-related genes and NSCLC, identifying IL1B as a risk factor and PLCG1 as a protective factor. We further demonstrate that AMBP may promote NSCLC progression partly through upregulating PLCG1 expression, with PLCG1 mediating 11.7% of this effect. These findings provide novel insights into pyroptosis regulation in NSCLC and highlight potential therapeutic targets.

PMID:
42888548
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.

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