铁死亡相关基因是潜在的治疗靶点，这些基因模型影响 NSCLC 患者的总生存期。

Background: Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSCC) are two of the most common subtypes of non-small cell lung cancer (NSCLC), with high mortality rates and rising incidence worldwide. Ferroptosis is a mode of programmed cell death caused by lipid peroxidation, the accumulation of reactive oxygen species, and is dependent on iron. The recent discovery of ferroptosis has provided new insights into tumor development, and the clinical relevance of ferroptosis for tumor therapy is being increasingly appreciated. However, its role in NSCLC remains to be explored. Methods: The clinical and molecular data for 1727 LUAD and LUSCC patients and 73 control individuals were obtained from the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database. Gene expression profiles, copy number variations and somatic mutations of 57 ferroptosis-related genes in 1727 tumor samples from the four datasets were used in a univariate Cox analysis and consensus clustering analysis. The biological signatures of each pattern were identified. A ferroptosis score was generated by combining the univariate Cox regression analysis and random forest algorithm followed by principal component analysis (PCA) and further investigated for its predictive and therapeutic value in LUAD and LUSCC. Results: The expression of 57 ferroptosis-related genes in NSCLC patients differed significantly from that of normal subjects. Based on unsupervised clustering of ferroptosis-related genes, we divided all patients into three ferroptosis expression pattern groups, which showed differences in ferroptosis-associated gene expression patterns, immune cell infiltration levels, prognostic characteristics and enriched pathways. Using the differentially expressed genes in the three ferroptosis expression patterns, a set of 17 ferroptosis-related gene prognostic models was established, which clustered all patients in the cohort into a low score group and a high score group, with marked differences in prognosis (p < 0.001). The high ferroptosis score was significantly associated with positive response to radiotherapy (p < 0.001), high T stage (p < 0.001), high N stage (p < 0.001) and high-grade tumor (p < 0.001) characteristics. Conclusions: The 17 ferroptosis-associated genes show great potential for stratifying LUAD and LUSCC patients into high and low risk groups. Interestingly, a high ferroptosis score in LUAD patients was associated with a good prognosis, whereas a similar high ferroptosis score in LUSCC patients was associated with a poor prognosis. Familiarity with the mechanisms underlying ferroptosis and its implications for the treatment of NSCLC, as well as its effect on OS and PFS, may provide guidance and insights in developing new therapeutic targets for NSCLC.

背景：肺腺癌（LUAD）和肺鳞状细胞癌（LUSCC）是非小细胞肺癌（NSCLC）中最常见的两种亚型，具有高死亡率和全球发病率上升的特点。铁死亡是一种由脂质过氧化、活性氧积累引起的程序性细胞死亡模式，依赖于铁。最近发现的铁死亡为肿瘤的发展提供了新的见解，铁死亡在肿瘤治疗中的临床相关性也越来越受到重视。然而，它在 NSCLC 中的作用仍有待探索。

方法：从基因表达综合数据库（GEO）和癌症基因组图谱（TCGA）数据库中获取了 1727 例 LUAD 和 LUSCC 患者和 73 例对照个体的临床和分子数据。在四个数据集的 1727 个肿瘤样本中，使用单变量 Cox 分析和共识聚类分析，对 57 个与铁死亡相关基因的基因表达谱、拷贝数变异和体细胞突变进行了分析。确定了每个模式的生物学特征。通过结合单变量 Cox 回归分析和随机森林算法，生成了铁死亡评分，然后进行主成分分析（PCA），并进一步探讨了其在 LUAD 和 LUSCC 中的预测和治疗价值。

结果：与正常个体相比，NSCLC 患者的 57 个与铁死亡相关基因的表达差异显著。基于铁死亡相关基因的无监督聚类，我们将所有患者分为三组铁死亡表达模式组，这三组在铁死亡相关基因表达模式、免疫细胞浸润水平、预后特征和富集途径上存在差异。使用三种铁死亡表达模式中的差异表达基因，建立了一组由 17 个与铁死亡相关的基因预后模型，该模型将队列中的所有患者聚类为低评分组和高评分组，预后差异显著（p<0.001）。高铁死亡评分与放疗的阳性反应（p<0.001）、高 T 期（p<0.001）、高 N 期（p<0.001）和高分级肿瘤（p<0.001）特征显著相关。

结论：这 17 个与铁死亡相关的基因具有很大的潜力，可以将 LUAD 和 LUSCC 患者分为高风险和低风险组。有趣的是，LUAD 患者的高铁死亡评分与较好的预后相关，而 LUSCC 患者的相似高铁死亡评分则与较差的预后相关。了解铁死亡的机制及其对 NSCLC 治疗的影响，以及对 OS 和 PFS 的影响，可能为 NSCLC 新的治疗靶点的开发提供指导和见解。