The effect and mechanism of NCOA4-mediated ferritinophagy in aluminum-induced ferroptosis of PC12 cells

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology Pub Date : 2025-08-13 DOI:10.1016/j.fct.2025.115699

Ruifeng Liang , Jiafen Zhang , Yan Luo , Yizhe Yang , Ting Zhou , Siyi Li , Jiawei Liu , Bingbing Zhang , Qiao Niu , Hongmei Zhang , Xiaojiang Qin , Junhong Gao

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Abstract

Aluminum (Al) can accumulate in the brain and cause significant neurotoxicity, with neuronal death being a major contributor to aluminum-induced cognitive decline. Recent studies highlight the involvement of Nuclear Receptor Coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis in this process, but their specific roles remain unclear. In this study, PC12 cells were treated with aluminum maltolate [Al(mal)₃], with or without deferoxamine (DFO), a ferroptosis inhibitor, to explore the role of ferroptosis in aluminum-induced toxicity. Ferritinophagy was further examined using 3-Methyladenine (3-MA) and small interfering RNA (siRNA) targeting NCOA4. Al(mal)₃ treatment increased intracellular iron, reactive oxygen species (ROS), and malondialdehyde (MDA) levels, while reducing glutathione (GSH), mitochondrial membrane potential (MMP), and glutathione peroxidase 4 (GPX4) expression—hallmarks of ferroptosis. DFO and inhibition of ferritinophagy reversed these effects. Moreover, suppression of NCOA4 restored ferritin levels and improved iron homeostasis. These findings suggest that aluminum may activate NCOA4-mediated ferritinophagy, leading to disrupted iron metabolism, oxidative stress, and ferroptosis in neuronal cells, thereby contributing to its neurotoxic effects.

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ncoa4介导的铁蛋白自噬在铝诱导的PC12细胞铁凋亡中的作用及机制

铝（Al）可以在大脑中积累并引起显著的神经毒性，神经元死亡是铝引起的认知能力下降的主要原因。最近的研究表明，核受体共激活因子4 （NCOA4）介导的铁蛋白吞噬和铁凋亡参与了这一过程，但它们的具体作用尚不清楚。在本研究中，用麦芽酸铝[Al(mal)3]处理PC12细胞，加或不加铁中毒抑制剂去铁胺（DFO），探讨铁中毒在铝诱导毒性中的作用。利用3-甲基腺嘌呤（3-MA）和靶向NCOA4的小干扰RNA （siRNA）进一步检测铁蛋白自噬。Al(mal)3处理增加了细胞内铁、活性氧（ROS）和丙二醛（MDA）水平，同时降低谷胱甘肽（GSH）、线粒体膜电位（MMP）和谷胱甘肽过氧化物酶4 （GPX4）的表达——铁下垂的标志。DFO和抑制铁蛋白吞噬逆转了这些作用。此外，抑制NCOA4可恢复铁蛋白水平并改善铁稳态。这些发现表明，铝可能激活ncoa4介导的铁蛋白自噬，导致神经元细胞铁代谢中断、氧化应激和铁凋亡，从而促进其神经毒性作用。

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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.