Druggable genome-wide Mendelian randomization integrating GWAS and eQTL/pQTL data identifies targets for lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is one of the most common types of non-small cell lung cancer with poor prognosis. Druggable genome-wide Mendelian randomization (MR) was conducted to discover LUSC-related targets using expression quantitative trait loci (eQTL) and protein QTL (pQTL) in the ieu_b_4953 dataset and finngen dataset. Bayesian co-localization analysis, summary‑data‑based MR (SMR) analysis, and HEIDI test were conducted to verify the causal associations between genes and LUSC risk. Prediction of prognosis and immune infiltration was performed at the transcriptomic level, and expression patterns of genes were analyzed at the single-cell level. We identified DNMT1, ACSS2, YBX1, SELENOS, PPARA, MST1, CPA4, and MPO as LUSC-related genes based on MR analysis. Although Bayesian co-localization analysis showed negative co-localization results (PPH3 + PPH4 < 0.8), positive SMR (p < 0.05) and HEIDI (p > 0.05) were found in the ieu_b_4953 dataset and finngen dataset. Blood CPA4 and DNMT1 might be protective factors for bladder cancer and allergic rhinitis, respectively. Patients with low expression of CPA4, DNMT1 and YBX1 had better prognosis, while patients with high expression of MST1 had better prognosis. Tumor samples exhibited reduced infiltration of CD4 cells, CD8 cells, activated dendritic cells, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, and mast cells. At the single-cell level, DNMT1, SELENOS and YBX1 were highly expressed in endothelial cells, epithelial cells, fibroblasts, hepatocytes, mast cells, and monocytes/macrophages. MST1 was overexpressed in hepatocytes. This study might deepen the understanding of the LUSC pathogenesis and identify potential targets for the management of LUSC.