背景：肺鳞状细胞癌（LSCC）是肺癌的主要亚型，预后差，生存率低。与肺腺癌相比，目前尚未发现FDA批准的针对肺鳞癌的靶向治疗方法。方法：为了确定 LSCC 的潜在药物靶点，使用基于汇总数据的孟德尔随机化 (SMR) 分析来检查 4,543 个可成药基因与 LSCC 之间的潜在关联，然后进行共定位分析和 HEIDI 测试以确认结果的稳健性。全表型关联研究（PheWAS）探讨了候选药物靶点的潜在副作用。富集分析和蛋白质-蛋白质相互作用网络揭示了治疗靶点的功能和意义。单细胞表达分析用于检查 LSCC 组织中可药物基因富集表达的细胞类型。药物预测包括筛选潜在的候选药物并通过分子对接评估它们与靶标的相互作用。结果：本研究通过全面的 SMR 分析确定了 LSCC 的 10 个重要药物靶点。这些目标包括（COPA、PKD2L1、CCR1、C2、CYP21A2 和 NCSTN 作为危险因素，CCNA2、C4A、APOM 和 LPAR2 作为保护因素）。 PheWAS 证明 C2、CCNA2、LPAR2 和 NCSTN 在基因水平上与其他表型存在关联。然后，我们通过 Dsigdb 数据库发现了四种可能有效的药物。随后，分子对接表明候选药物和潜在靶分子之间存在有利的结合相互作用。在成药性评价中，十分之五的药物靶基因已用于药物开发（APOM、C4A、CCNA2、COPA和PKD2L1）。十分之六的可药物基因在 LSCC 组织中显示出显着表达（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则富集在巨噬细胞和上皮细胞中。结论：我们的研究揭示了 10 个潜在的 LSCC 治疗药物基因，这可能有助于推进 LSCC 的精确有效的治疗方法。版权所有 © 2024 Wu、Chen、Wen 和 Zhang。

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.Copyright © 2024 Wu, Chen, Wen and Zhang.