Vespakinin-M delineates an AMPK/mTOR-arginine-TCA cycle axis to act as an immunometabolic switch in post-stroke microglia.

Overview

Authors: Dexiao Wang^1,2, Jingyu Zhang^1,2, Zhejun Zhuang^1,2, Qian Wang^1,2, Jie Li^1,2, Xue Wang^1,2, Kunkun Li^1,2, Yunyun Liu^1,2, Yanhui Cao^1,2, Lijuan Li^1,3, Yunwu Zhang⁴, Yu Zhao^1,2, Yingjun Zhao⁴, Hairong Zhao^1,4,2, Chenggui Zhang^1,2

ORCID iDs: Chenggui Zhang

Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, 671000, China
National-Local Joint Engineering Research Center of Entomoceutics, Dali, 671000, China
The First Affiliated Hospital of Dali University, Dali University, Dali, Yunnan, 671000, China
Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China

Institutions: Dali University (China); Xiamen University (China); First Affiliated Hospital of Xiamen University (China)

Journal: Redox biology, volume 94, article 104210

Dates: received 3 April 2026; accepted 10 May 2026; published online 12 May 2026; in print July 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1016/j.redox.2026.104210 · PMID 42166856 · PMCID PMC13214344 · OpenAlex W7161111469

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: mouse (organism), stroke (population), cellular / molecular (subfield)

Methods: Statistics, Smoothing, state filtering, decompositions

Keywords: Vespakinin-M, Ischemic stroke, Microglia, Mitochondrial dysfunction, Immunometabolism, Arginine metabolism

MeSH: AMP-Activated Protein Kinases*, Arginine*, Microglia*, Stroke*, TOR Serine-Threonine Kinases*, Animals, Citric Acid Cycle, Disease Models, Animal, Energy Metabolism, Metabolic Reprogramming, Mice, Mitochondria, Neuroprotective Agents, Oxidative Phosphorylation, Oxidative Stress, Signal Transduction (* major topic)

Topic: Neuroinflammation and Neurodegeneration Mechanisms (Neurology, Neuroscience), according to OpenAlex

Funding: Yunnan Provincial Natural Science Foundation (202305AC160036, 202401AS070029, 202501AT070422); National Natural Science Foundation of China (82560786, 82160798, 82471446); Xiamen University

Citations: cited by 1 paper (Europe PMC); 65 references in the paper

Abstract

Despite advances in recanalization therapy for ischemic stroke, effective neuroprotection against cerebral ischemia-reperfusion injury (CIRI) remains an unmet need, largely due to persistent microglia-driven neuroinflammation and associated oxidative stress. Vespakinin-M (VK) is a naturally neuroprotective peptide isolated from wasp venom that can cross the blood-brain barrier. Although VK has been shown to improve functional outcomes in preliminary stroke models, its underlying mechanisms remain unclear. Here, we show that administration of VK alleviates neuroinflammation and oxidative damage in a mouse stroke model. This neuroprotection is orchestrated by microglial metabolic reprogramming, which shifts their energy metabolism from aerobic glycolysis toward oxidative phosphorylation (OXPHOS) and their functional phenotype from pro-inflammatory M1 to reparative M2. Integrated multi-omics and isotopic tracing uncover that VK redirects arginine metabolism to generate fumarate. This directly couples amino acid catabolism with the tricarboxylic acid (TCA) cycle, thereby restoring mitochondrial bioenergetics and redox balance. Mechanistically, VK activates the energy sensor AMPK while inhibiting the anabolic regulator mTOR. AMPK knockdown partially abolishes the beneficial effects of VK, establishing the AMPK/mTOR axis as the upstream regulator of this arginine-centric metabolic rewiring. Interestingly, VK retains the ability to stimulate de novo arginine synthesis even under arginine-deprived conditions, and its efficacy is synergistically enhanced with arginine supplementation. Together, these findings define an immunometabolic axis—AMPK/mTOR-arginine-TCA cycle coupling—that dictates microglial fate after stroke, and suggests VK as a therapeutic agent capable of concurrently targeting neuroinflammation, mitochondrial dysfunction, and metabolic imbalance.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

figshare:32171751, at figshare; found in “Data availability”

Data availability

The data will be made available upon reasonable request. Raw flow cytometry data (.fcs files) are available in figshare (https://doi.org/10.6084/m9.figshare.32171751). The raw data underlying the main figures have been compiled as Dataset 1 and are provided as a supplementary file. Uncropped Western blot images are included in the Supplementary Information, along with supplementary methods and supplementary figures.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

Authors: added Chenggui Zhang (0000-0002-2691-5079); removed Chenggui Zhang

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 15 authors, 6 keywords, 16 MeSH terms, 3 funders, 65 references.

Cite

This paper

Wang, D., Zhang, J., Zhuang, Z., Wang, Q., Li, J., Wang, X., Li, K., Liu, Y., Cao, Y., Li, L., Zhang, Y., Zhao, Y., Zhao, Y., Zhao, H., & Zhang, C. (2026). Vespakinin-M delineates an AMPK/mTOR-arginine-TCA cycle axis to act as an immunometabolic switch in post-stroke microglia. Redox biology, 94, 104210. https://doi.org/10.1016/j.redox.2026.104210

BibTeX

@article{wang2026vespakinin, author = {Wang, Dexiao and Zhang, Jingyu and Zhuang, Zhejun and Wang, Qian and Li, Jie and Wang, Xue and Li, Kunkun and Liu, Yunyun and Cao, Yanhui and Li, Lijuan and Zhang, Yunwu and Zhao, Yu and Zhao, Yingjun and Zhao, Hairong and Zhang, Chenggui}, title = {{Vespakinin-M delineates an AMPK/mTOR-arginine-TCA cycle axis to act as an immunometabolic switch in post-stroke microglia}}, journal = {Redox biology}, year = {2026}, month = may, volume = {94}, pages = {104210}, publisher = {Elsevier}, issn = {2213-2317}, doi = {10.1016/j.redox.2026.104210}, url = {https://doi.org/10.1016/j.redox.2026.104210}, pmid = {42166856}, pmcid = {PMC13214344} }

RIS

TY - JOUR AU - Wang, Dexiao AU - Zhang, Jingyu AU - Zhuang, Zhejun AU - Wang, Qian AU - Li, Jie AU - Wang, Xue AU - Li, Kunkun AU - Liu, Yunyun AU - Cao, Yanhui AU - Li, Lijuan AU - Zhang, Yunwu AU - Zhao, Yu AU - Zhao, Yingjun AU - Zhao, Hairong AU - Zhang, Chenggui TI - Vespakinin-M delineates an AMPK/mTOR-arginine-TCA cycle axis to act as an immunometabolic switch in post-stroke microglia T2 - Redox biology J2 - Redox Biol PY - 2026 DA - 2026/05/12 VL - 94 SP - 104210 SN - 2213-2317 PB - Elsevier DO - 10.1016/j.redox.2026.104210 UR - https://doi.org/10.1016/j.redox.2026.104210 LA - en ER -

CSL-JSON

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