SFXN1 Reduction Alleviates Cerebral Ischemia–Reperfusion Injury by Promoting Neuronal Survival and Reducing Neuroinflammation

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-05-26 DOI:10.1111/cns.70457

Xiangyu Xu, Zhongying Duan, Xin Zhou, Rui Zhao, Jing Xu, Zhaolong Zhang, Mengfei Lv, Qi Wan, Yu Cui

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引用次数: 0

Abstract

Aim

Sideroflexin 1 (SFXN1) is an important inner mitochondrial membrane protein that regulates many physiological and pathological events. However, the role of SFXN1 in cerebral ischemia–reperfusion (I/R)-induced neuronal death remains unclear.

Methods

We employed in vivo injury models of transient middle cerebral artery occlusion (tMCAO) and in vitro models of lipopolysaccharide (LPS) stimulation and oxygen–glucose deprivation/reperfusion (OGD/R) to investigate the regulatory effects of SFXN1 on neuroinflammation and brain injury. Western blotting, immunofluorescence, and real-time quantitative PCR were utilized to assess SFXN1 expression, proinflammatory signaling pathways activation, and cytokine levels in vitro. Cerebral infarction was evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining and Nissl staining.

Results

SFXN1 expression was upregulated following cerebral I/R injury. Both neurons and microglia exhibited increased SFXN1 expression after oxygen–glucose deprivation/reoxygenation (OGD/R) treatment. SFXN1 knockdown reduced OGD/R-induced neuronal death and alleviated cerebral I/R injury. Additionally, conditioned medium from SFXN1-knockdown microglia reduced neurotoxicity in vitro. Mechanistically, SFXN1 induced mitochondrial dysfunction and neuronal death after OGD/R in an iron-independent manner. Furthermore, SFXN1 promoted the production of proinflammatory cytokines by promoting NF-κB activation, partially through iron transport in microglia after OGD/R.

Conclusion

This study reveals the novel role of SFXN1 in exacerbating cerebral I/R injury by reducing neuronal survival through the modulation of mitochondrial function and promotion of microglia-mediated neuroinflammation via NF-κB activation.

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SFXN1还原通过促进神经元存活和减少神经炎症减轻脑缺血再灌注损伤

目的Sideroflexin 1 （SFXN1）是一种重要的线粒体内膜蛋白，可调控许多生理和病理事件。然而，SFXN1在脑缺血再灌注（I/R）诱导的神经元死亡中的作用尚不清楚。方法采用短暂性大脑中动脉闭塞（tMCAO）的体内损伤模型和脂多糖（LPS）刺激和氧糖剥夺/再灌注（OGD/R）的体外模型，研究SFXN1对神经炎症和脑损伤的调节作用。采用Western blotting、免疫荧光和实时定量PCR检测SFXN1体外表达、促炎信号通路激活和细胞因子水平。采用2,3,5-三苯四氮唑（TTC）染色和尼氏染色评价脑梗死。结果SFXN1在脑I/R损伤后表达上调。在氧-葡萄糖剥夺/再氧化（OGD/R）处理后，神经元和小胶质细胞的SFXN1表达均增加。SFXN1敲低可减轻OGD/R诱导的神经元死亡，减轻脑I/R损伤。此外，sfxn1敲除小胶质细胞的条件培养基在体外降低了神经毒性。机制上，SFXN1以铁不依赖的方式诱导OGD/R后线粒体功能障碍和神经元死亡。此外，SFXN1通过促进NF-κB活化促进促炎细胞因子的产生，部分通过OGD/R后小胶质细胞中的铁转运。结论SFXN1通过调节线粒体功能、激活NF-κB促进小胶质细胞介导的神经炎症，从而降低神经元存活，从而加重脑I/R损伤。

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

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.