通过药物靶点基因组整合分析揭示肺鳞状细胞癌潜在药物靶点

背景：肺鳞状细胞癌（LSCC）是肺癌的主要亚型之一，预后差、存活率低。与肺腺癌相比，尚未有FDA批准的针对性治疗药物用于LSCC。方法：为识别潜在药物靶点，采用摘要数据基础的孟德尔随机化（SMR）分析，探讨4,543个药物靶点基因与LSCC的潜在关联，随后通过共定位分析和HEIDI检验确认结果的稳健性。全表型关联分析（PheWAS）用于探索候选药物靶点的潜在副作用。富集分析和蛋白质相互作用网络揭示治疗靶点的功能和意义。单细胞表达分析检测在LSCC组织中富集表达药物靶点的细胞类型。药物预测通过筛选潜在药物候选物及其与靶点的相互作用进行分子对接。结果：本研究通过全面的SMR分析，筛选出10个与LSCC相关的显著药物靶点，包括（COPA、PKD2L1、CCR1、C2、CYP21A2、NCSTN作为风险因素，C CNA2、C4A、APOM、LPAR2作为保护因素）。PheWAS显示，C2、CCNA2、LPAR2和NCSTN在遗传水平上与其他表型相关。随后，用Dsigdb数据库筛选出4个潜在有效药物。分子对接显示药物候选与潜在靶点分子之间具有良好的结合作用。在药物靶向性评估中，十个靶点基因中有五个已用于药物开发（APOM、C4A、CCNA2、COPA、PKD2L1）。六个药物靶点基因在LSCC组织中表达显著（COPA、PKD2L1、CCR1、C2、NCSTN、LPAR2）。此外，单细胞表达分析显示，C2和CCNA2主要富集在巨噬细胞中，而COPA和NCSTN则在巨噬细胞和上皮细胞中均有表达。结论：本研究揭示了10个潜在的药物靶点基因，为LSCC的精准和高效治疗提供了潜在的靶点。

Background: Lung squamous cell carcinoma (LSCC) is a major subtype of lung cancer with poor prognosis and low survival rate. Compared with lung adenocarcinoma, yet no FDA-approved targeted-therapy has been found for lung squamous cell carcinoma. Methods: To identify potential drug targets for LSCC, Summary-data-based Mendelian randomization (SMR) analysis was used to examine the potential association between 4,543 druggable genes and LSCC, followed by colocalization analysis and HEIDI tests to confirm the robustness of the result. Phenome-wide association study (PheWAS) explored potential side effects of candidate drug targets. Enrichment analysis and protein-protein interaction networks revealed the function and significance of therapeutic targets. Single-cell expression analysis was used to examine cell types with enrichment expression of druggable genes in LSCC tissue. Drug prediction included screening potential drug candidates and evaluating their interactions with targets through molecular docking. Results: This research has identified ten significant drug targets for LSCC through a comprehensive SMR analysis. These targets included (COPA, PKD2L1, CCR1, C2, CYP21A2, and NCSTN as risk factors, and CCNA2, C4A, APOM, and LPAR2 as protective factors). PheWAS demonstrated that C2, CCNA2, LPAR2, and NCSTN exhibited associations with other phenotypes at the genetic level. Then, we found four potentially effective drugs with the Dsigdb database. Subsequently, molecular docking indicated that favorable binding interactions between drug candidates and potential target molecules. In the druggability evaluation, five out of ten drug target genes have been used in drug development (APOM, C4A, CCNA2, COPA, and PKD2L1). Six out of ten druggable genes showed significant expression in LSCC tissues (COPA, PKD2L1, CCR1, C2, NCSTN, LPAR2). Besides, Single-cell expression analysis revealed that C2 and CCNA2 were primarily enriched in macrophages, while COPA and NCSTN were enriched in both macrophages and epithelial cells. Conclusion: Our research revealed ten potential druggable genes for LSCC treatment, which might help to advance the precise and efficient therapeutic approaches of LSCC.