通过整合可药物基因组和全基因组关联数据，揭示了肺鳞状细胞癌的潜在药物靶标

背景：肺鳞状细胞癌（LSCC）是肺癌的主要亚型，预后较差，存活率较低。与肺腺癌相比，尚未发现FDA批准的靶向疗法用于肺鳞状细胞癌。方法：为了确定LSCC的潜在药物靶标，使用基于DATA的Mendelian随机分析（SMR）分析来检查4,543个可药物基因与LSCC之间的潜在关联，然后进行共定位分析和Heidi测试以确认结果的鲁棒性。全球整个关联研究（PHEWAS）探讨了候选药物靶标的潜在副作用。富集分析和蛋白质 - 蛋白质相互作用网络揭示了治疗靶标的功能和意义。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其与靶标的相互作用。结果：这项研究通过全面的SMR分析确定了LSCC的十个重要药物靶标。这些目标包括（COPA，PKD2L1，CCR1，C2，CYP21A2和NCSTN作为风险因素，CCNA2，C4A，APOM和LPAR2作为保护因素）。 Phewas表明C2，CCNA2，LPAR2和NCSTN在遗传水平上表现出与其他表型的关联。然后，我们发现了使用DSIGDB数据库的四种潜在有效的药物。随后，分子对接表明，药物候选物与潜在靶标分子之间的有利结合相互作用。在药物测定性评估中，十分之五的药物靶基因已用于药物开发（APOM，C4A，CCNA2，COPA和PKD2L1）。十分之六的可药基因在LSCC组织中显示出显着的表达（Copa，PKD2L1，CCR1，C2，C2，NCSTN，LPAR2）。此外，单细胞表达分析表明，C2和CCNA2主要富集在巨噬细胞中，而CopA和NCSTN富含巨噬细胞和上皮细胞。结论：我们的研究揭示了十个潜在的LSCC治疗基因，这可能有助于推进LSCC的精确和有效的治疗方法。

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.