胃癌 (GC) 仍然是全球主要的健康威胁，位居第五位最常见的癌症。缺氧是实体瘤的一个特征，显着促进GC的恶性进展。线粒体是缺氧损伤的主要目标，缺氧损伤会在包括胃癌在内的癌症发展过程中促进线粒体功能障碍。然而，基于缺氧和线粒体功能障碍相关基因（HMDRGs）预测胃癌预后的基因特征和预后模型尚未建立。胃癌患者的基因表达谱数据集来自癌症基因组图谱和基因表达综合数据库。使用最小绝对收缩和选择算子 Cox (LASSO-Cox) 回归分析来选择预后基因，以构建预后模型。通过 ESTIMATE、CIBERSORT 和 ssGSEA 分析评估免疫浸润。利用肿瘤免疫功能障碍和排斥（TIDE）和免疫表型评分（IPS）来探索免疫治疗的影响。此外，还进行了体外实验来验证 HMDRG 在 GC 细胞恶性肿瘤中的功能作用。在这项研究中，确定了 5 个 HMDRG（ZFP36、SERPINE1、DUSP1、CAV1 和 AKAP12）用于开发 GC 的预后模型。该模型根据中位风险评分将 GC 患者分为高风险组和低风险组。构建了预测总生存期 (OS) 的列线图，并显示与观察到的 OS 一致的结果。免疫浸润分析表明，高危人群的个体往往表现出免疫细胞浸润增加。此外，对癌症免疫治疗反应的分析表明，与低风险组患者相比，高风险组患者对癌症免疫治疗的反应较差。免疫组织化学（IHC）染色显示，GC患者中HMDRGs的表达水平与GC显着相关，其中SERPINE1表达上调最显着，而ZFP36表达下调最显着。此外，体外研究证实 SERPINE1 和 ZFP36 有助于与线粒体功能障碍相关的 GC 细胞的恶性过程。这项研究提出了一种评估 GC 预后和免疫治疗效果的新颖有效的方法，并为了解 GC 的发病机制提供了见解。版权所有 © 2024 李、崔、王、王、余、熊。

Gastric cancer (GC) remains a major global health threat ranking as the fifth most prevalent cancer. Hypoxia, a characteristic feature of solid tumors, significantly contributes to the malignant progression of GC. Mitochondria are the major target of hypoxic injury that promotes mitochondrial dysfunction during the development of cancers including GC. However, the gene signature and prognostic model based on hypoxia- and mitochondrial dysfunction-related genes (HMDRGs) in the prediction of GC prognosis have not yet been established.The gene expression profile datasets of stomach cancer patients were retrieved from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Prognostic genes were selected using Least Absolute Shrinkage and Selection Operator Cox (LASSO-Cox) regression analysis to construct a prognostic model. Immune infiltration was evaluated through ESTIMATE, CIBERSORT, and ssGSEA analyses. Tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS) were utilized to explore implications for immunotherapy. Furthermore, in vitro experiments were conducted to validate the functional roles of HMDRGs in GC cell malignancy.In this study, five HMDRGs (ZFP36, SERPINE1, DUSP1, CAV1, and AKAP12) were identified for developing a prognostic model in GC. This model stratifies GC patients into high- and low-risk groups based on median risk scores. A nomogram predicting overall survival (OS) was constructed and showed consistent results with observed OS. Immune infiltration analysis indicated that individuals in the high-risk group tend to exhibit increased immune cell infiltration. Additionally, analysis of cancer immunotherapy responses revealed that high-risk group patients exhibit poorer responses to cancer immunotherapy compared to the low-risk group. Immunohistochemistry (IHC) staining indicated that the expression levels of HMDRGs were remarkably correlated with GC, of which, SERPINE1 displayed the most pronounced up-regulation, while ZFP36 exhibited the most notable down-regulation in GC patients. Furthermore, in vitro investigation validated that SERPINE1 and ZFP36 contribute to the malignant processes of GC cells correlated with mitochondrial dysfunction.This study presents a novel and efficient approach to evaluate GC prognosis and immunotherapy efficacy, and also provides insights into understanding the pathogenesis of GC.Copyright © 2024 Li, Cui, Wang, Wang, Yu and Xiong.