中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (8): 2245-2263.doi: 10.4103/NRR.NRR-D-24-00025

• 综述:退行性病与再生 • 上一篇    下一篇

神经元衰老相关神经退行性疾病中调节性细胞死亡：关键通路和治疗潜力

  

  • 出版日期:2025-08-15 发布日期:2024-12-12

Neuronal regulated cell death in aging-related neurodegenerative diseases: key pathways and therapeutic potentials

Run Song1, 2, Shiyi Yin1, 2, Jiannan Wu2 , Junqiang Yan1, 2, *   

  1. 1 Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China;  2 Neuromolecular Biology Laboratory, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
  • Online:2025-08-15 Published:2024-12-12
  • Contact: Junqiang Yan, MD, PhD, yanjq@haust.edu.cn.
  • Supported by:
    This work was supported by the Key Projects of Medical Science and Technology of Henan Province, No. SBGJ202002099 (to JY).

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摘要：

调节性细胞死亡（如凋亡、坏死、焦亡、铜死亡、铁死亡、双硫死亡等）涉及复杂的信号通路和分子效应子，已被证明是调节神经细胞衰老死亡的重要调节机制。然而过度激活调节性细胞死亡可能导致衰老相关疾病的进展。在过去的10年间，新发现的有关铁和铜积累的金属调节机制在神经退行性疾病中诱导细胞死亡的作用引起了广泛关注。为此，此次综述系统地总结了神经细胞死亡凋亡、坏死、焦亡、铁死亡和自噬这5种主要调节性细胞死亡在衰老相关神经退行性疾病中的存在形式和新机制，还探索了最近提出的2种新型调节性细胞死亡类型：铜死亡和二硫死亡，此外还深入研究了靶向衰老相关疾病的各种调节性细胞死亡的关键通路以及分子串扰调节机制，探索不同调节性细胞死亡的的重叠点和关键节点。在分子水平上探索调控调节性细胞死亡以靶向、治疗和预防衰老相关神经退行性疾病的靶点。

https://orcid.org/0000-0002-6489-2824 (Junqiang Yan); https://orcid.org/0000-0001-9535-7296 (Run Song); 

https://orcid.org/0000-0002-5116-7973 (Shiyi Yin); https://orcid.org/0000-0001-6018-4612 (Jiannan Wu)

关键词: 铜死亡, 二硫死亡, 铁死亡, 泛凋亡, 自噬, 细胞凋亡, 坏死, 焦亡, 神经退行性疾病, 神经老化疾病

Abstract: Regulated cell death (such as apoptosis, necroptosis, pyroptosis, autophagy, cuproptosis, ferroptosis, disulfidptosis) involves complex signaling pathways and molecular effectors, and has been proven to be an important regulatory mechanism for regulating neuronal aging and death. However, excessive activation of regulated cell death may lead to the progression of aging-related diseases. This review summarizes recent advances in the understanding of seven forms of regulated cell death in age-related diseases. Notably, the newly identified ferroptosis and cuproptosis have been implicated in the risk of cognitive impairment and neurodegenerative diseases. These forms of cell death exacerbate disease progression by promoting inflammation, oxidative stress, and pathological protein aggregation. The review also provides an overview of key signaling pathways and crosstalk mechanisms among these regulated cell death forms, with a focus on ferroptosis, cuproptosis, and disulfidptosis. For instance, FDX1 directly induces cuproptosis by regulating copper ion valency and dihydrolipoamide S-acetyltransferase aggregation, while copper mediates glutathione peroxidase 4 degradation, enhancing ferroptosis sensitivity. Additionally, inhibiting the Xc- transport system to prevent ferroptosis can increase disulfide formation and shift the NADP+ /NADPH ratio, transitioning ferroptosis to disulfidptosis. These insights help to uncover the potential connections among these novel regulated cell death forms and differentiate them from traditional regulated cell death mechanisms. In conclusion, identifying key targets and their crosstalk points among various regulated cell death pathways may aid in developing specific biomarkers to reverse the aging clock and treat age-related neurodegenerative conditions.

Key words: apoptosis, autophagy, cuproptosis, disulfidptosis, ferroptosis, necroptosis, neurodegenerative disease, neurological aging diseases, PANoptosis, pyroptosis