低氧参与肿瘤生物过程和疾病进展，而铁死亡作为一种新发现的程序性细胞死亡过程，与乳腺癌（BC）的发生和发展密切相关。然而，在BC中基于低氧和铁死亡的可靠预后标志尚未被开发。我们将癌症基因组图谱（TCGA）乳腺癌队列设为训练集，将乳腺癌国际分子分类（METABRIC）BC队列设为验证集。使用最小绝对缩减和选择算子（LASSO）和COX回归方法来构建铁死亡相关基因（FRG）和低氧相关基因（HRG）预测标志（HFRS）。使用CIBERSORT算法和ESTIMATE评分来探索HFRS与肿瘤免疫微环境之间的关系。免疫组化染色用于检测组织样本中的蛋白质表达。我们开发了一个诊断模型用于进一步推进HFRS标志的临床应用。在TCGA BC队列中筛选了10个与铁死亡相关的基因和低氧相关基因，构建了HFRS预测标志，并在METABRIC BC队列中验证了其预测能力。具有高HFRS的BC患者具有更短的存活时间，更高的肿瘤分期和更高的淋巴结阳性率。此外，高HFRS与高低氧、铁死亡和免疫抑制状态相关。构建了一个根据年龄、分期和HFRS标志的诊断模型，具有预测BC患者总体生存（OS）的强大预测能力。我们开发了一个新颖的预测模型，包括低氧和铁死亡相关的基因，以预测BC患者的OS，并表征其免疫微环境，为临床决策和个体化治疗提供了新的治疗方法。版权所有©2023 Zhong，Shen，Zhou，Yu，Wang，Sun，Wang和Liu。

Hypoxia is involved in tumor biological processes and disease progression. Ferroptosis, as a newly discovered programmed cell death process, is closely related to breast cancer (BC) occurrence and development. However, reliable prognostic signatures based on a combination of hypoxia and ferroptosis in BC have not been developed.We set The Cancer Genome Atlas (TCGA) breast cancer cohort as training set and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) BC cohort as the validation set. Least Absolute Shrinkage and Selection Operator (LASSO) and COX regression approaches were used to construct ferroptosis-related genes (FRGs) and hypoxia-related genes (HRGs) prognostic signature (HFRS). The CIBERSORT algorithm and ESTIMATE score were used to explore the relationship between HFRS and tumor immune microenvironment. Immunohistochemical staining was used to detect protein expression in tissue samples. A nomogram was developed to advance the clinical application of HFRS signature.Ten ferroptosis-related genes and hypoxia-related genes were screened to construct the HFRS prognostic signature in TCGA BC cohort, and the predictive capacity was verified in METABRIC BC cohort. BC patients with high-HFRS had shorter survival time, higher tumor stage, and a higher rate of positive lymph node. Moreover, high HFRS was associated with high hypoxia, ferroptosis, and immunosuppression status. A nomogram that was constructed with age, stage, and HFRS signature showed a strong prognostic capability to predict overall survival (OS) for BC patients.We developed a novel prognostic model with hypoxia and ferroptosis-related genes to predict OS, and characterize the immune microenvironment of BC patients, which might provide new cures for clinical decision-making and individual treatment of BC patients.Copyright © 2023 Zhong, Shen, Zhou, Yu, Wang, Sun, Wang and Liu.