Shen Yanxin, Zhang Guimei, Wei Chunxiao, Zhao Panpan, Wang Yongchun, Li Mingxi, Sun Li
Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China.
Cognitive Impairment Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China.
Neural Regen Res. 2025 Mar 1;20(3):613-631. doi: 10.4103/NRR.NRR-D-23-01343. Epub 2024 Mar 1.
Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer's disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer's disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer's disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer's disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer's disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer's disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer's disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer's disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer's disease.
阿尔茨海默病是一种与年龄相关的神经退行性疾病，其发病机制复杂且尚未完全明确。尽管进行了广泛研究，但尚未找到治愈阿尔茨海默病的方法。氧化应激介导过度的氧化反应，其作为原发性或继发性病理事件参与阿尔茨海默病发病机制已被广泛接受。作为含硒抗氧化酶家族的一员，谷胱甘肽过氧化物酶4将酯化磷脂氢过氧化物还原以维持细胞氧化还原稳态。随着铁死亡的发现，谷胱甘肽过氧化物酶4在包括阿尔茨海默病在内的几种疾病的抗脂质过氧化中的核心作用受到广泛关注。越来越多的证据表明，阿尔茨海默病患者大脑中谷胱甘肽过氧化物酶4的表达受到抑制，导致氧化应激、炎症、铁死亡和细胞凋亡，这些都与阿尔茨海默病的病理损伤密切相关。几种治疗方法，如小分子药物、天然植物产品和非药物治疗，通过促进谷胱甘肽过氧化物酶4的表达和增强其活性来改善阿尔茨海默病的病理损伤和认知功能。因此，上调谷胱甘肽过氧化物酶4可能是治疗阿尔茨海默病的一种有前景的策略。本文综述了谷胱甘肽过氧化物酶4的基因结构、生物学功能和调控机制，讨论了谷胱甘肽过氧化物酶4在与阿尔茨海默病密切相关的病理事件中的重要作用，并总结了针对谷胱甘肽过氧化物酶4治疗阿尔茨海默病的小分子药物、天然植物产品和非药物疗法的研究进展。此前关于该主题的大多数研究使用动物模型，缺乏相关临床研究。未来需要进行临床试验以验证靶向谷胱甘肽过氧化物酶4的策略在治疗阿尔茨海默病中的疗效。
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