铁死亡和细胞焦亡的联合构建用于预测肝细胞癌的预后分类器和免疫景观、化疗疗效和免疫抑制分子。

BACKGROUND: The induction of ferroptosis and pyroptosis has been highlighted as a novel approach to decide cancer cell fate. However, few studies have systematically explored the role of combining these two novel cell death modalities in hepatocellular carcinoma (HCC). METHODS: Ferroptosis-related genes (FRGs) and pyroptosis-related genes (PRGs) were retrieved and downloaded from FerrDb and GeneCards database, respectively. A prognostic classifier integrating with prognostic differentially expressed FRGs and PRGs was constructed by the least absolute shrinkage and selection operator (LASSO) algorithm in the TCGA-LIHC dataset and verified using the ICGC (LIRI-JP) dataset. RESULTS: A total of 194 differentially expressed FRGs and PRGs were identified and named as differentially expressed genes (DEGs) and, out of them 79 were found dramatically correlated with prognosis in HCC. Based on 13 key DEGs with prognostic value, a novel expression signature was constructed and used to stratify HCC patients into 2 groups. Kaplan-Meier analysis demonstrated that high-risk patients had a more dismal prognosis. Receiver operating characteristic curve (ROC) and multivariate Cox analysis confirmed its predictive power and independent characteristic. Immune profile analysis demonstrated that high-risk group had prominent upregulation of immunosuppressive cells, including macrophages, Th2_cells and Treg. The correlation analysis between this signature and immunosuppressive molecules, Immunophenoscore (IPS) and chemotherapeutic efficacy demonstrated that low-risk group had a higher IC50 of cisplatin, mitomycin and doxorubicin and negatively related with CTLA4, HAVCR2, LAG3, PDCD1, TIGIT and ICIs treatment represented by CTLA4-/PD-1-, CTLA4 + /PD-1-, CTLA4-/PD-1 + . CONCLUSIONS: In this research, a novel expression signature was identified based on FRGs and PRGs in HCC, and this signature could be used to predict prognosis and select patients potentially benefiting from immunotherapies and chemotherapy.

背景：诱导铁死亡和细胞焦亡已被强调为决定癌细胞命运的一种新方法。然而，很少有研究系统地探讨联合使用这两种新型细胞死亡方式在肝细胞癌（HCC）中的作用。

方法：从 FerrDb 和 GeneCards 数据库中分别检索和下载铁死亡相关基因（FRGs）和细胞焦亡相关基因（PRGs）。利用 TCGA-LIHC 数据集的最小绝对收缩和选择算子（LASSO）算法构建一个整合预后差异表达 FRGs 和 PRGs 的预后分类器，并在 ICGC（LIRI-JP）数据集上进行验证。

结果：共鉴定出 194 个差异表达 FRGs 和 PRGs，并命名为差异表达基因（DEGs），其中 79 个基因与 HCC 的预后显著相关。基于具有预后价值的 13 个关键 DEGs，构建了一个新的表达谱，用于将 HCC 患者分为 2 组。Kaplan-Meier 分析表明，高危患者的预后更差。接受者操作特征曲线（ROC）和多变量 Cox 分析证实了其预测能力和独立性特征。免疫谱分析表明，高危组中免疫抑制细胞（包括巨噬细胞、Th2 细胞和 Treg）的上调更为显著。该特征与免疫抑制分子、免疫表型评分（IPS）和化疗疗效的相关性分析表明，低危组顺铂、丝裂霉素和阿霉素的 IC50 更高，与 CTLA4、HAVCR2、LAG3、PDCD1、TIGIT 和以 CTLA4-/PD-1-、CTLA4+/PD-1-、CTLA4-/PD-1+ 为代表的免疫检查点抑制剂治疗呈负相关。

结论：本研究基于 HCC 中的 FRGs 和 PRGs 鉴定了一个新的表达谱，该表达谱可用于预测预后，并选择可能受益于免疫治疗和化疗的患者。