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

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.