Zhang Hongjiao, Zhan Jinbo, Zhou Juanjuan, Liu Liping, He Yan, Le Yi, Liu Weiqi, Zhou Ling, Liu Yawen, Xiang Xiaojun
Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, Jiangxi Province, P.R. China.
Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang 330006, Jiangxi, China.
Carcinogenesis. 2025 Apr 3;46(2). doi: 10.1093/carcin/bgaf030.
Currently, research on ferroptosis-related prognostic models for gastric cancer is limited, whereas traditional predictive models often have a narrow perspective and low accuracy. In this study, we systematically analyzed the expression patterns of ferroptosis-related genes in patients with gastric adenocarcinoma and evaluated their prognostic value. Using data from The Cancer Genome Atlas (TCGA) and the FerrDb database, we developed a ferroptosis-related prognostic risk model based on four genes: hydroxycarboxylic acid receptor 1 (HCAR1), branched-chain amino acid transaminase 1 (BCAT1), ceruloplasmin (CP), and dickkopf-1 (DKK1). This model demonstrated strong prognostic value and potential clinical relevance in stratifying gastric cancer patients by overall survival outcomes. ferroptosis-related prognostic risk model. Compared to traditional clinicopathological features, the risk score derived from this model exhibited superior predictive accuracy for overall survival in patients with gastric cancer and served as an independent prognostic factor. Functional enrichment analysis revealed that the risk score was primarily enriched for extracellular matrix-related pathways. Additionally, the risk score was significantly correlated with TME signature genes, immune checkpoint expression, and immune cell infiltration in stomach adenocarcinoma (STAD). Mechanistic studies revealed that HCAR1 is abnormally overexpressed in gastric cancer tissues and is associated with a poor prognosis. It exerted its effects by regulating the GPX4/SLC7A11 axis to inhibit lipid peroxidation and malondialdehyde accumulation, thereby obstructing ferroptosis. Experimental validation demonstrated that the downregulation of HCAR1 promoted ferroptosis and suppressed malignant tumor phenotypes, suggesting that both the gene and its associated risk model hold significant clinical value as potential therapeutic targets and prognostic biomarkers.
目前，关于胃癌铁死亡相关预后模型的研究有限，而传统的预测模型往往视角狭窄且准确性低。在本研究中，我们系统地分析了胃腺癌患者中铁死亡相关基因的表达模式，并评估了它们的预后价值。利用来自癌症基因组图谱（TCGA）和FerrDb数据库的数据，我们基于四个基因：羟基羧酸受体1（HCAR1）、支链氨基酸转氨酶1（BCAT1）、铜蓝蛋白（CP）和 Dickkopf-1（DKK1），开发了一个铁死亡相关的预后风险模型。该模型在通过总生存结果对胃癌患者进行分层方面显示出强大的预后价值和潜在的临床相关性。铁死亡相关的预后风险模型。与传统的临床病理特征相比，该模型得出的风险评分在预测胃癌患者总生存方面表现出更高的准确性，并作为一个独立的预后因素。功能富集分析表明，风险评分主要富集在细胞外基质相关通路。此外，风险评分与胃腺癌（STAD）中的肿瘤微环境特征基因、免疫检查点表达和免疫细胞浸润显著相关。机制研究表明，HCAR1在胃癌组织中异常高表达，并与不良预后相关。它通过调节GPX4/SLC7A11轴发挥作用，抑制脂质过氧化和丙二醛积累，从而阻碍铁死亡。实验验证表明，HCAR1的下调促进了铁死亡并抑制了恶性肿瘤表型，这表明该基因及其相关的风险模型作为潜在的治疗靶点和预后生物标志物具有重要的临床价值。
