NR4A1 Exerts Pro-Tumor Role in Glioblastoma via Inducing xCT/GPX4-Regulated Ferroptosis.

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Annals of Clinical and Translational Neurology Pub Date : 2025-10-06 DOI:10.1002/acn3.70173

Peng Tao, Shikuan Din, Zhengkang Fu, Qian Sun, Xiwei Zhu, Yuxin Wei, Huan Qu, Xinyi Zhang, Jiaxuan Liu, Chuhua Fu, Qianxue Chen

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引用次数: 0

Abstract

Purpose: This study investigates NR4A1's paradoxical roles in glioblastoma (GBM) progression, focusing on its mechanistic link to ferroptosis regulation. We aimed to resolve conflicting reports of NR4A1 as both an oncogene and a tumor suppressor by defining its transcriptional control over xCT/GPX4-mediated iron homeostasis and its clinical relevance in glioma survival.

Methods: TCGA cohort analysis (n = 163) correlated NR4A1 expression with survival endpoints (OS/PFI/DSS, log-rank p < 0.05). Functional validation employed U87/U251 GBM models for viability (CCK-8), proliferation (EdU/colony formation), and migration assays (Transwell/wound healing). RNA sequencing (DESeq2, FDR < 0.05) and ChIP-qPCR identified NR4A1-xCT transcriptional regulation. Ferroptosis was quantified via lipid peroxidation (MDA/GSH/Fe²⁺ ELISA, C11 BODIPY), while Western blotting mapped the NR4A1/xCT/GPX4/P53 axis. Orthotopic xenografts (n = 6/group) evaluated therapeutic efficacy using biweekly tumor volumetry. All data were analyzed in triplicate (GraphPad Prism 8.0; t-test/ANOVA, *p < 0.05).

Conclusion: NR4A1 drives GBM progression by transcriptionally activating xCT/GPX4 to suppress ferroptosis. Dual targeting of NR4A1 and ferroptosis pathways synergistically inhibits tumor growth (64% reduction vs. controls, p = 0.008), providing a mechanistic rationale for overcoming therapy resistance in GBM.

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NR4A1通过诱导xCT/ gpx4调控的铁凋亡在胶质母细胞瘤中发挥促瘤作用。

目的：本研究探讨NR4A1在胶质母细胞瘤（GBM）进展中的矛盾作用，重点研究其与铁凋亡调节的机制联系。我们的目的是通过确定NR4A1对xCT/ gpx4介导的铁稳态的转录控制及其在胶质瘤存活中的临床相关性，来解决NR4A1作为致癌基因和肿瘤抑制基因的相互矛盾的报道。方法：TCGA队列分析（n = 163）将NR4A1表达与生存终点（OS/PFI/DSS, log-rank p2 + ELISA, C11 BODIPY）相关，而Western blotting绘制NR4A1/xCT/GPX4/P53轴。原位异种移植物（n = 6/组）通过双周肿瘤体积测量评估治疗效果。所有数据一式三份（GraphPad Prism 8.0； t检验/方差分析，*p）进行分析。结论：NR4A1通过转录激活xCT/GPX4抑制铁凋亡来驱动GBM进展。双重靶向NR4A1和铁下垂途径协同抑制肿瘤生长（与对照组相比减少64%，p = 0.008），为克服GBM治疗耐药提供了机制基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)

CiteScore

9.10

自引率

1.90%

发文量

218

审稿时长

8 weeks

期刊介绍： Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.