Artemisinin inhibits neuronal ferroptosis in Alzheimer's disease models by targeting KEAP1

doi:10.1038/s41401-024-01378-6

科研成果详情

题名	Artemisinin inhibits neuronal ferroptosis in Alzheimer's disease models by targeting KEAP1
作者	Deng, Peng-xi 1,2,3; Silva, Marta 1; Yang, Na 4; Wang, Qing 5; Meng, Xin 1,6; Ye, Ke-qiang 6; Gao, Hong-chang2,3; Zheng, Wen-hua 1
发表日期	2024-09-09
发表期刊	ACTA PHARMACOLOGICA SINICA 影响因子和分区
语种	英语
原始文献类型	Article ; Early Access
关键词	Alzheimer's disease artemisinin ferroptosis KEAP1 Nrf2 hippocampus
其他关键词	MILD COGNITIVE IMPAIRMENT ; GLUTATHIONE-PEROXIDASE 4 ; ACTIVATION ; PATHWAY ; CELLS ; NRF2 ; PROTECTS ; ABLATION ; DECLINE ; BRAIN
摘要	Ferroptosis, a form of cell death characterized by lipid peroxidation, is involved in neurodegenerative diseases such as Alzheimers disease (AD). Recent studies have shown that a first-line antimalarial drug artemisinin is effective to counteract AD pathology. In this study, we investigated the protective effect of artemisinin against neuronal ferroptosis and the underlying mechanisms. In hippocampal HT22 cells, pretreatment with artemisinin dose-dependently protected against Erastin-induced cell death with an EC50 value of 5.032 mu M, comparable to the ferroptosis inhibitor ferrostatin-1 (EC50 = 4.39 mu M). We demonstrated that artemisinin (10 mu M) significantly increased the nuclear translocation of Nrf2 and upregulated SLC7A11 and GPX4 in HT22 cells. Knockdown of Nrf2, SLC7A11 or GPX4 prevented the protective action of artemisinin, indicating that its anti-ferroptosis effect is mediated by the Nrf2-SLC7A11-GPX4 pathway. Molecular docking and Co-Immunoprecipitation (Co-IP) analysis revealed that artemisinin competitively binds with KEAP1, promoting the dissociation of KEAP1-Nrf2 complex and inhibiting the ubiquitination of Nrf2. Intrahippocampal injection of imidazole-ketone-Erastin (IKE) induced ferroptosis in mice accompanied by cognitive deficits evidenced by lower preference for exploration of new objects and new object locations in the NOR and NOL tests. Artemisinin (5, 10 mg/kg, i.p.) dose-dependently inhibited IKE-induced ferroptosis in hippocampal CA1 region and ameliorated learning and memory impairments. Moreover, we demonstrated that artemisinin reversed A beta 1-42-induced ferroptosis, lipid peroxidation and glutathione depletion in HT22 cells, primary hippocampal neurons, and 3xTg mice via the KEAP1-Nrf2 pathway. Our results demonstrate that artemisinin is a novel neuronal ferroptosis inhibitor that targets KEAP1 to activate the Nrf2-SLC7A11-GPX4 pathway.
资助项目	National Natural Science Foundation of China [32070969, 22274115]; Science and Technology Development Fund, Macao SAR [0104/2022/A2, 0038/2020/AMJ]; Guangdong, Hong Kong and Macao Joint Key Laboratory forNew Drug Screening (GDSTC) [EF2023-00054-FHS]; Guangdong Provincial Funding Committee for Basic and Applied Fundamental Research (2022-Natural Science Foundation, GDSTC) [EF019/FHS-ZWH/2022]; University of Macau [MYRG-CRG2024-00019-FHS, MYRG-GRG2023-00118-FHS-UMDF, MYRG2022-00154-FHS]
出版者	NATURE PUBL GROUP
ISSN	1671-4083
EISSN	1745-7254
DOI	10.1038/s41401-024-01378-6
页数	12
WOS类目	Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
WOS记录号	WOS:001308269800001
收录类别	SCIE ; PUBMED
URL	查看原文
PubMed ID	39251858
通讯作者地址	[Zheng, Wen-hua]Univ Macau, Fac Hlth Sci, Dept Pharmaceut Sci, Taipa 999078, Macao, Peoples R China. ; [Gao, Hong-chang]Oujiang Lab, Zhejiang Lab Regenerat Med Vis & Brain Hlth, Wenzhou 325035, Peoples R China. ; [Gao, Hong-chang]Wenzhou Med Univ, Inst Metabon & Med NMR, Sch Pharmaceut Sci, Wenzhou 325035, Peoples R China.
TOP期刊	TOP期刊
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/218572
专题	附属第二医院_核磁共振室
通讯作者	Gao, Hong-chang; Zheng, Wen-hua
作者单位	1.Univ Macau, Fac Hlth Sci, Dept Pharmaceut Sci, Taipa 999078, Macao, Peoples R China; 2.Oujiang Lab, Zhejiang Lab Regenerat Med Vis & Brain Hlth, Wenzhou 325035, Peoples R China; 3.Wenzhou Med Univ, Inst Metabon & Med NMR, Sch Pharmaceut Sci, Wenzhou 325035, Peoples R China; 4.Tongji Univ, Shanghai Peoples Hosp 10, Dept Cardiol, Sch Med, Shanghai 200040, Peoples R China; 5.Southern Med Univ, Dept Neurol, Zhujiang Hosp, Guangzhou 510280, Peoples R China; 6.Chinese Acad Sci, Fac Life & Hlth Sci, Shenzhen Inst Adv Technol SIAT, Shenzhen 518055, Peoples R China
第一作者单位	附属第二医院_核磁共振室
通讯作者单位	附属第二医院_核磁共振室
推荐引用方式 GB/T 7714	Deng, Peng-xi,Silva, Marta,Yang, Na,et al. Artemisinin inhibits neuronal ferroptosis in Alzheimer's disease models by targeting KEAP1[J]. ACTA PHARMACOLOGICA SINICA,2024.
APA	Deng, Peng-xi., Silva, Marta., Yang, Na., Wang, Qing., Meng, Xin., ... & Zheng, Wen-hua. (2024). Artemisinin inhibits neuronal ferroptosis in Alzheimer's disease models by targeting KEAP1. ACTA PHARMACOLOGICA SINICA.
MLA	Deng, Peng-xi,et al."Artemisinin inhibits neuronal ferroptosis in Alzheimer's disease models by targeting KEAP1".ACTA PHARMACOLOGICA SINICA (2024).