Caffeine improves hypoxia/reoxygenation induced neuronal cell injury through inhibiting cellular ferroptosis: an in vitro study.

IF 1.7 4区 医学 Q3 CLINICAL NEUROLOGY
Neurological Research Pub Date : 2025-04-01 Epub Date: 2025-02-25 DOI:10.1080/01616412.2025.2470714
Haizhen Jia, Huajun Fan, Jiarui Liang, Runqing He
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引用次数: 0

Abstract

Objective: Ferroptosis, a regulated cell death pathway driven by lipid peroxidation and iron overload, is implicated in neuronal injury caused by hypoxia/reoxygenation (H/R). Caffeine, a widely consumed psychoactive compound, has shown neuroprotective effects in various central nervous system disorders, but its role in regulating ferroptosis remains unclear. This study investigates the neuroprotective effects of caffeine on ferroptosis and its regulation of ACSL4, a key ferroptosis-related protein.

Methods: Molecular docking was performed to evaluate the interaction between caffeine and ferroptosis-related proteins ACSL4 and GPX4. HT-22 cells were subjected to H/R to establish an in vitro injury model, followed by treatment with caffeine at varying concentrations. ACSL4 was silenced or overexpressed to explore its role in caffeine-mediated ferroptosis regulation. Cell viability, inflammatory cytokines, ferroptosis markers, and mitochondrial function were assessed.

Results: Molecular docking revealed favorable binding affinities of caffeine with ACSL4 (-5.6 kcal/mol) and GPX4 (-4.6 kcal/mol). Caffeine treatment dose-dependently improved cell viability, reduced TNF-α, IL-1β, and IL-6 levels, and inhibited ferroptosis by downregulating ACSL4 and upregulating GPX4. Overexpression of ACSL4 reversed these protective effects, increasing lipid peroxidation markers (iron, Fe2+, ROS, and MDA) and reducing GSH levels and mitochondrial membrane potential. Conversely, silencing ACSL4 enhanced caffeine's protective effects, confirming its role as a critical target of caffeine-mediated ferroptosis inhibition.

Conclusion: Caffeine protects against H/R-induced neuronal injury by regulating ACSL4-mediated ferroptosis, reducing oxidative stress and inflammation. These findings highlight ACSL4 as a therapeutic target and provide mechanistic insights into caffeine's neuroprotective potential.

咖啡因通过抑制细胞铁下垂改善缺氧/再氧化诱导的神经元细胞损伤:一项体外研究。
目的:铁凋亡是一种由脂质过氧化和铁超载驱动的受调控的细胞死亡途径,与缺氧/再氧化(H/R)引起的神经元损伤有关。咖啡因是一种广泛使用的精神活性化合物,已显示出对各种中枢神经系统疾病的神经保护作用,但其在调节铁下垂中的作用尚不清楚。本研究探讨了咖啡因对铁中毒的神经保护作用及其对铁中毒相关蛋白ACSL4的调节作用。方法:采用分子对接的方法研究咖啡因与凋亡相关蛋白ACSL4和GPX4的相互作用。将HT-22细胞进行H/R处理,建立体外损伤模型,然后用不同浓度的咖啡因处理。ACSL4被沉默或过表达,以探索其在咖啡因介导的铁下垂调节中的作用。评估细胞活力、炎症细胞因子、铁下垂标志物和线粒体功能。结果:分子对接显示咖啡因与ACSL4 (-5.6 kcal/mol)和GPX4 (-4.6 kcal/mol)具有良好的结合亲和力。咖啡因剂量依赖性地提高细胞活力,降低TNF-α、IL-1β和IL-6水平,并通过下调ACSL4和上调GPX4抑制铁下垂。过表达ACSL4逆转了这些保护作用,增加了脂质过氧化标志物(铁、Fe2+、ROS和MDA),降低了GSH水平和线粒体膜电位。相反,沉默ACSL4增强了咖啡因的保护作用,证实了其作为咖啡因介导的铁下垂抑制的关键靶点的作用。结论:咖啡因通过调节acsl4介导的铁下垂、减少氧化应激和炎症反应,对H/ r诱导的神经元损伤具有保护作用。这些发现突出了ACSL4作为治疗靶点,并为咖啡因的神经保护潜力提供了机制上的见解。
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来源期刊
Neurological Research
Neurological Research 医学-临床神经学
CiteScore
3.60
自引率
0.00%
发文量
116
审稿时长
5.3 months
期刊介绍: Neurological Research is an international, peer-reviewed journal for reporting both basic and clinical research in the fields of neurosurgery, neurology, neuroengineering and neurosciences. It provides a medium for those who recognize the wider implications of their work and who wish to be informed of the relevant experience of others in related and more distant fields. The scope of the journal includes: •Stem cell applications •Molecular neuroscience •Neuropharmacology •Neuroradiology •Neurochemistry •Biomathematical models •Endovascular neurosurgery •Innovation in neurosurgery.
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