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Peer-reviewedCC BYFrontiers in Molecular Neuroscience

Synergistic regulation of neuroinflammation by mitophagy and the cGAS–STING pathway following ischemic stroke

  • Yu Xiao1
  • Yu Xiao2
  • Peijie Fu1
  • Peijie Fu2
  • Chun Zhao3
  • Wenqi Song1
  • Wenqi Song2
  • Yutao Lu1
  • Yutao Lu2
  • Huiqin Wang2
  • Huiqin Wang4
  • Xiaoping Yin1
5 more authors
  • Xiaoping Yin2
  • Zhiying Chen1
  • Zhiying Chen2
  • Yuanyuan Xiang2
  • Yuanyuan Xiang5
5 affiliations
  1. 1Department of Neurology, Clinical Medical College of Jiujiang University, Jiujiang, Jiangxi, China
  2. 2Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
  3. 3Gastrointestinal Surgery Department, Third People's Hospital of Jiujiang City, Jiujiang, Jiangxi, China
  4. 4College of Stomatology, Jiujiang University, Jiujiang, Jiangxi, China
  5. 5Department of Plastic Surgery, Clinical Medical College of Jiujiang University, Jiujiang, Jiangxi, China
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Abstract

Neuroinflammation is widely recognized as a major driver of secondary brain injury following ischemic stroke. Recent studies have shown that mitochondrial dysfunction-induced mitochondrial DNA (mtDNA) release is one of the key mechanisms activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Mitophagy, as a quality control mechanism maintaining mitochondrial homeostasis, selectively clears damaged mitochondria, thereby limiting the leakage of abnormal mtDNA. Although previous reviews have outlined the general framework of the mitophagy-cGAS-STING interaction in neuroinflammation, this review places it within the specific context of ischemic stroke. It integrates the cell type-specificity of the neurovascular unit, explores both synergistic and interactive aspects, and evaluates targeted nanotherapeutic strategies. This article aims to explore the potential synergistic role of mitophagy and the cGAS-STING pathway in the pathological progression of ischemic stroke. First, the article elaborates on mitophagy and mitophagy-dependent regulation of neuroinflammation, highlighting its role in suppressing cGAS-STING activation by preventing mtDNA leakage. Second, it examines the cGAS-STING signaling pathway in neuroinflammation, with particular attention to cGAS-STING activation across neurovascular unit cell types (microglia, neurons, astrocytes, endothelial cells). Third, the functional synergy and potential molecular crosstalk between mitophagy and the cGAS–STING pathway in neuroinflammation are discussed. Finally, the article summarizes the potential therapeutic strategies targeting mitophagy and the cGAS-STING pathway, and further explores the emerging potential of microenvironment-responsive intelligent nanoplatforms to enhance drug delivery efficiency and multidimensional synergistic mechanisms by targeting the cGAS-STING pathway and mitochondria, thereby achieving precise immune regulation and improving therapeutic efficacy. This paper provides a mechanistic perspective on immune intervention for ischemic stroke and lays a theoretical foundation for future clinical translation strategies.

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Cite

BibTeXRIS
BibTeX
@article{xiao2026synergistic,
  title = {{Synergistic regulation of neuroinflammation by mitophagy and the cGAS–STING pathway following ischemic stroke}},
  author = {Yu Xiao and Yu Xiao and Peijie Fu and Peijie Fu and Chun Zhao and Wenqi Song and Wenqi Song and Yutao Lu and Yutao Lu and Huiqin Wang and Huiqin Wang and Xiaoping Yin and Xiaoping Yin and Zhiying Chen and Zhiying Chen and Yuanyuan Xiang and Yuanyuan Xiang},
  journal = {Frontiers in Molecular Neuroscience},
  year = {2026},
  month = oct,
  doi = {10.3389/fnmol.2026.1990236},
  url = {https://doi.org/10.3389/fnmol.2026.1990236},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Synergistic regulation of neuroinflammation by mitophagy and the cGAS–STING pathway following ischemic stroke
AU  - Yu Xiao
AU  - Yu Xiao
AU  - Peijie Fu
AU  - Peijie Fu
AU  - Chun Zhao
AU  - Wenqi Song
AU  - Wenqi Song
AU  - Yutao Lu
AU  - Yutao Lu
AU  - Huiqin Wang
AU  - Huiqin Wang
AU  - Xiaoping Yin
AU  - Xiaoping Yin
AU  - Zhiying Chen
AU  - Zhiying Chen
AU  - Yuanyuan Xiang
AU  - Yuanyuan Xiang
PY  - 2026
DA  - 2026/10/26
JO  - Frontiers in Molecular Neuroscience
DO  - 10.3389/fnmol.2026.1990236
UR  - https://doi.org/10.3389/fnmol.2026.1990236
AB  - Neuroinflammation is widely recognized as a major driver of secondary brain injury following ischemic stroke. Recent studies have shown that mitochondrial dysfunction-induced mitochondrial DNA (mtDNA) release is one of the key mechanisms activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Mitophagy, as a quality control mechanism maintaining mitochondrial homeostasis, selectively clears damaged mitochondria, thereby limiting the leakage of abnormal mtDNA. Although previous reviews have outlined the general framework of the mitophagy-cGAS-STING interaction in neuroinflammation, this review places it within the specific context of ischemic stroke. It integrates the cell type-specificity of the neurovascular unit, explores both synergistic and interactive aspects, and evaluates targeted nanotherapeutic strategies. This article aims to explore the potential synergistic role of mitophagy and the cGAS-STING pathway in the pathological progression of ischemic stroke. First, the article elaborates on mitophagy and mitophagy-dependent regulation of neuroinflammation, highlighting its role in suppressing cGAS-STING activation by preventing mtDNA leakage. Second, it examines the cGAS-STING signaling pathway in neuroinflammation, with particular attention to cGAS-STING activation across neurovascular unit cell types (microglia, neurons, astrocytes, endothelial cells). Third, the functional synergy and potential molecular crosstalk between mitophagy and the cGAS–STING pathway in neuroinflammation are discussed. Finally, the article summarizes the potential therapeutic strategies targeting mitophagy and the cGAS-STING pathway, and further explores the emerging potential of microenvironment-responsive intelligent nanoplatforms to enhance drug delivery efficiency and multidimensional synergistic mechanisms by targeting the cGAS-STING pathway and mitochondria, thereby achieving precise immune regulation and improving therapeutic efficacy. This paper provides a mechanistic perspective on immune intervention for ischemic stroke and lays a theoretical foundation for future clinical translation strategies.
SN  - 1662-5099
ER  -