Targeting <i>Atf4</i> for enhanced neuroprotection: Role of quercetin-loaded EVs in ischemic stroke

Lanqing Zhao; Yu Chen; Xiaoxu Ding; Hongxi Li; Jinwei Li

doi:10.1016/j.jpha.2025.101312

Volume 15 Issue 9

Sep. 2025

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Lanqing Zhao, Yu Chen, Xiaoxu Ding, Hongxi Li, Jinwei Li. Targeting Atf4 for enhanced neuroprotection: Role of quercetin-loaded EVs in ischemic stroke[J]. Journal of Pharmaceutical Analysis, 2025, 15(9): 101312. doi: 10.1016/j.jpha.2025.101312

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Lanqing Zhao, Yu Chen, Xiaoxu Ding, Hongxi Li, Jinwei Li. Targeting Atf4 for enhanced neuroprotection: Role of quercetin-loaded EVs in ischemic stroke[J]. Journal of Pharmaceutical Analysis, 2025, 15(9): 101312. doi: 10.1016/j.jpha.2025.101312

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Targeting Atf4 for enhanced neuroprotection: Role of quercetin-loaded EVs in ischemic stroke

doi: 10.1016/j.jpha.2025.101312

a. Department of Sleep Medicine Center, Shengjing Hospital of China Medical University, Shenyang, 110004, China;
b. Department of Otorhinolaryngology Head and Neck, Shengjing Hospital of China Medical University, Shenyang, 110004, China;
c. Department of Pain Management, Shengjing Hospital of China Medical University, Shenyang, 110004, China;
d. Department of Neurology and Stroke Center, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, 110001, China

Funds:

This study was supported by Liaoning Xingliao Talent Program, China (Grant No.: YXMJ-JC-05). Figs. 1A and 9 were created using BioRender.com.

Received Date: Oct. 08, 2024
Accepted Date: Apr. 10, 2025
Rev Recd Date: Mar. 29, 2025
Publish Date: Sep. 30, 2025

Abstract

Abstract

This study investigates the neuroprotective potential of extracellular vesicles (EVs) delivering quercetin-3-O-β-d-glucuronic acid (QG-EVs) in cerebral ischemia-reperfusion injury (CIRI). Targeted brain delivery of QG-EVs was confirmed, with neuron cells identified as pivotal in modulating CIRI through single-cell RNA sequencing (scRNA-seq). Activating transcription factor 4 (Atf4) was highlighted as a critical regulatory factor, and in vitro studies revealed that silencing Atf4 diminished the neuroprotective effects of QG-EVs, increasing oxidative stress levels and neuronal apoptosis. In a CIRI mouse model, the knockdown of Atf4 attenuated the protective outcomes provided by QG-EVs, further affirming the role of Atf4 in mediating neuroprotection. Behavioral assessments and protein analysis showed that QG-EVs significantly reduced neuronal damage and pro-apoptotic markers, while improving neurological function via Atf4 upregulation. The outcomes hint at the potential of QG-EVs as a beneficial therapeutic modality to mitigate neuronal damage in CIRI by enhancing Atf4 expression, highlighting its potential for improving ischemic stroke outcomes.
- Quercetin-3-O-β-d-glucuronic acid,
- Cerebral ischemia-reperfusion injury,
- Extracellular vesicles,
- Atf4,
- Neuroprotection,
- Oxidative stress

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References(47)

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