发现铁死亡在肺部的多种病理情况中都有参与。对铁死亡相关基因进行基因工程可能为肺腺癌（LUAD）的治疗提供潜在靶点。从FerrDb数据库中收集了9个铁死亡调节基因和标志物，并根据癌症基因组图谱（TCGA）-LUAD队列数据进行了体细胞突变和表达分析。利用最小绝对值收缩和选择算子（LASSO）和Cox回归分析筛选与铁死亡显著相关的基因。利用TCGA-LUAD队列数据构建了铁死亡相关基因签名，并使用GSE队列的汇总数据（GSE30219、GSE31210、GSE37745和GSE50081）进行验证。对铁死亡相关基因签名中的基因进行免疫微环境成分和突变分析。所有9个铁死亡调节基因和标志物在正常的LUAD肿瘤组织和相邻正常组织间表达差异显著，并与拷贝数变异相关。在TCGA-LUAD数据集中，1329个基因的表达与9个铁死亡调节基因和标志物显著相关，其中5个基因（ALDOA、PLK1、CD47、CENPC和TMOD3）被整合到一个铁死亡相关基因签名中，用于计算LUAD样本的风险评分，与免疫细胞浸润程度和免疫评分显著相关。分子对接显示了天然活性化合物槲皮素与靶蛋白ALDOA和CD47的结合活性，以及马兜铃酸与PLK1蛋白和TMOD3蛋白的结合活性。本研究构建了一个具有LUAD预后预测价值的铁死亡相关基因签名，其中的基因是LUAD的潜在治疗靶点。槲皮素和马兜铃酸是通过直接与这些靶点结合并显示高亲和力和强稳定性的潜在抑制剂候选物。© 2023 John Wiley & Sons Ltd.

The involvement of ferroptosis has been found in many pathological conditions of the lung. The genetic engineering of ferroptosis-related genes may provide a potential target for the treatment of lung adenocarcinoma (LUAD).Nine ferroptosis regulators and markers were collected from FerrDb and their somatic mutations and expressions were analyzed based on The Cancer Genome Atlas (TCGA)-LUAD cohort data. Least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were performed to screen genes significantly associated with ferroptosis. The ferroptosis-related gene signature was constructed using TCGA-LUAD cohort data and was verified using the GSE cohort with pooled data for GSE30219, GSE31210, GSE37745 and GSE50081. Immune microenvironment component and mutation analysis were performed for genes in the ferroptosis-related gene signature.All nine ferroptosis regulators and markers were differentially expressed between normal LUAD tumor tissues and adjacent normal tissues and were related to copy number variation. The expression of 1329 genes were significantly associated with nine ferroptosis regulators and markers in the TCGA-LUAD dataset, five (ALDOA, PLK1, CD47, CENPC and TMOD3) of which were integrated into a ferroptosis-related gene signature to calculate the risk score of LUAD samples, showing a significant correlation with the abundance of immune cell infiltration and the immune score. Molecular docking showed the binding activity of natural active compound quercetin to target proteins ALDOA and CD47, as well as the binding activity of aristolochic acid to PLK1 protein and TMOD3 protein.In the present study, a ferroptosis-related gene signature with predictive value for LUAD prognosis was constructed, in which the gene was a potential therapeutic target for LUAD. Quercetin and aristolochic acid were potential candidates for inhibiting these targets by directly binding to them and showing high affinity and strong stability.© 2023 John Wiley & Sons Ltd.