Piceatannol upregulates USP14-mediated GPX4 deubiquitination to inhibit neuronal ferroptosis caused by cerebral ischemia-reperfusion in mice

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY Food and Chemical Toxicology Pub Date : 2025-01-27 DOI:10.1016/j.fct.2025.115281

Qiuju Zhao , Xinya Wang , Taiyu Zhang , Shuxian Guo , Xiaojia Liu , Shihao Wan , Yani Guo , Qiannuo Zhang , Jinshui Li , Shaohua Wang , Liuyi Dong

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Abstract

Ischemic stroke is a very common brain disorder. This study aims to assess the neuroprotective effects of piceatannol (PCT) in preventing neuronal injury resulting from cerebral ischemia and reperfusion (I/R) in mice. Additionally, we investigated the underlying mechanisms through which PCT inhibits neuronal ferroptosis by modulating the USP14/GPX4 signaling axis. In vitro and in vivo experiments were conducted. In vitro, oxygen-glucose deprivation followed by reoxygenation (OGD/R) was used to simulate ischemic injury in neuronal cells. We utilized various techniques, including DCFH-DA staining, FeRhoNox-1 staining, MDA and GSH determination, immunofluorescence, Western blotting, co-immunoprecipitation, plasmid and siRNA transfection, to evaluate the therapeutic efficacy of PCT and elucidate its mechanism of action. For vivo studies, we established a mouse model of I/R by ligating the bilateral common carotid arteries. The efficacy of PCT in mitigating brain injury and cognitive dysfunction were assessed through behavioral tests, histological analysis, Western blotting, and immunohistochemistry. PCT treatment significantly enhanced cell viability under OGD/R and reduced lipid peroxidation by decreasing levels of ROS, MDA. Furthermore, PCT effectively inhibited neuronal ferroptosis by modulating the expression of key ferroptosis-related proteins, including GPX4, ACSL4, FPN1, and Ferritin. Mechanistically, PCT was found to prevent GPX4 degradation through USP14-mediated deubiquitination. Notably, silencing USP14 reversed the ferroptotic effects of PCT, whereas overexpressing of USP14 amplified these effects. In vivo, PCT significantly reduced pathological damage of brain tissue and improved cognitive dysfunction. Piceatannol exerts neuroprotective effects by regulating ferroptosis through the USP14/GPX4 axis, thereby preventing cerebral ischemia/reperfusion injury.

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皮杉醇上调usp14介导的GPX4去泛素化，抑制小鼠脑缺血再灌注所致的神经元铁凋亡。

缺血性中风是一种非常常见的脑部疾病。本研究旨在探讨picetanol （PCT）对小鼠脑缺血再灌注（I/R）所致神经元损伤的神经保护作用。此外，我们还研究了PCT通过调节USP14/GPX4信号轴抑制神经元铁下垂的潜在机制。进行了体外和体内实验。体外采用氧-葡萄糖剥夺-再氧合（OGD/R）模拟神经元细胞缺血损伤。我们利用DCFH-DA染色、FeRhoNox-1染色、MDA和GSH测定、免疫荧光、Western blotting、共免疫沉淀、质粒和siRNA转染等多种技术评价PCT的治疗效果并阐明其作用机制。在体内研究中，我们通过结扎双侧颈总动脉建立了小鼠I/R模型。通过行为试验、组织学分析、免疫印迹和免疫组织化学评价PCT减轻脑损伤和认知功能障碍的疗效。PCT处理可显著提高OGD/R下的细胞活力，并通过降低ROS、MDA水平降低脂质过氧化。此外，PCT通过调节GPX4、ACSL4、FPN1和铁蛋白等关键铁凋亡相关蛋白的表达，有效抑制神经元铁凋亡。机制上，发现PCT通过usp14介导的去泛素化来阻止GPX4降解。值得注意的是，USP14的沉默逆转了PCT的铁猝变效应，而USP14的过表达则放大了这些效应。在体内，PCT显著减轻了脑组织病理损伤，改善了认知功能障碍。皮杉醇通过USP14/GPX4轴调节铁下沉，发挥神经保护作用，从而防止脑缺血再灌注损伤。

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来源期刊

Food and Chemical Toxicology 工程技术-毒理学

CiteScore

10.90

自引率

4.70%

发文量

651

审稿时长

31 days

期刊介绍： Food and Chemical Toxicology (FCT), an internationally renowned journal, that publishes original research articles and reviews on toxic effects, in animals and humans, of natural or synthetic chemicals occurring in the human environment with particular emphasis on food, drugs, and chemicals, including agricultural and industrial safety, and consumer product safety. Areas such as safety evaluation of novel foods and ingredients, biotechnologically-derived products, and nanomaterials are included in the scope of the journal. FCT also encourages submission of papers on inter-relationships between nutrition and toxicology and on in vitro techniques, particularly those fostering the 3 Rs. The principal aim of the journal is to publish high impact, scholarly work and to serve as a multidisciplinary forum for research in toxicology. Papers submitted will be judged on the basis of scientific originality and contribution to the field, quality and subject matter. Studies should address at least one of the following: -Adverse physiological/biochemical, or pathological changes induced by specific defined substances -New techniques for assessing potential toxicity, including molecular biology -Mechanisms underlying toxic phenomena -Toxicological examinations of specific chemicals or consumer products, both those showing adverse effects and those demonstrating safety, that meet current standards of scientific acceptability. Authors must clearly and briefly identify what novel toxic effect (s) or toxic mechanism (s) of the chemical are being reported and what their significance is in the abstract. Furthermore, sufficient doses should be included in order to provide information on NOAEL/LOAEL values.