ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1666225
This article is part of the Research TopicImmune Landscape in the Transition from Inflammation to TumorigenesisView all 8 articles
Zinc alleviates stroke development through autophagy-mediated modulation of immune microenvironment
Provisionally accepted
Zijie Qiu1Xin Liu1Jie Li1Hongming Yin1Jiankun Luo1Zigang Lin1Mayire Rexiati2Adila Abulaiti2Aikebaier yasen2Dilihumaer Aili2bing Meng1Lifei Xing1Xiaoqi Li1Zhenhua You1Jiaxin He1Chaowen Huang1*Zhenzhu Qian1*
Jialong Chen1*- 1The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, China
- 2Kashi University, Kashgar, China
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Abstract Background: Stroke is a leading cause of death and long-term disability worldwide and is increasingly recognized as a neuroinflammatory, immune-mediated disease. Acute ischemia triggers robust activation and infiltration of innate immune cells, exacerbating neuronal injury. Zinc is an essential micronutrient with known immunomodulatory and autophagy-regulating roles, but its impact on stroke-driven neuroinflammation remains unclear. We aimed to investigate whether zinc protects against ischemic brain injury by modulating autophagy and the immune microenvironment. Methods: Genome-wide association (GWAS) and NHANES cohort analyses were performed to assess the association between zinc intake levels and stroke risk. Pathway enrichment analysis, PPI network construction, and diagnostic modeling were undertaken to identify ZIARs (zinc-responsive immuno-autophagic regulators). Immune infiltration analysis was used to assess immune cell infiltration levels in stroke. Cell-based ischemia-reperfusion experiments were conducted to evaluate zinc's effects on autophagy and neuronal cell injury. Results: Higher zinc levels were associated with lower stroke prevalence, as supported by GWAS results (OR ~0.141) and NHANES findings (adjusted OR ~0.96). Zinc-associated genes were predominantly enriched in autophagy and inflammatory signaling pathways, including PI3K-Akt and NF-κB. The diagnostic model identified ZIARs whose expression was closely linked to immune cell composition, particularly neutrophil infiltration, in stroke. In vitro experiment, zinc pretreatment of hypoxia-stressed neurons reduced cell death and oxidative damage, whereas autophagy inhibition abolished zinc’s neuroprotective effect. qPCR and Western blot analyses further confirmed that zinc attenuates RELA-driven autophagy overactivation, thereby promoting neuronal survival. Conclusion: Zinc confers neuroprotection in ischemic stroke by restoring autophagic flux and suppressing excessive innate inflammation through regulation of ZIARs. These findings underscore zinc's neuroprotective role via immune-autophagy crosstalk and position it as a potential strategy for stroke prevention and intervention. Keywords: Stroke; Neuroinflammation; Zinc; Autophagy; Immune cell; Micronutrients
Keywords: Stroke, Neuroinflammation, Zinc, Autophagy, immune cell, Micronutrients
Received: 15 Jul 2025; Accepted: 21 Aug 2025.
Copyright: © 2025 Qiu, Liu, Li, Yin, Luo, Lin, Rexiati, Abulaiti, yasen, Aili, Meng, Xing, Li, You, He, Huang, Qian and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Chaowen Huang, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, China
Zhenzhu Qian, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, China
Jialong Chen, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, China
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