The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication
- 1Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan China
- 2Department of Critical Care Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, Sichuan China
Abstract
Neurodegenerative disorders involve a strong inflammatory component, yet the underlying inflammatory mechanisms may be heterogeneous across disease stage, cell type, and systemic context. A key unresolved question is how cellular and systemic stress is converted into sustained neuroinflammation. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate DNA-sensing hub that translates mislocalized self-DNA - derived from mitochondrial stress and mtDNA leakage, nuclear envelope instability, micronuclei formation, or impaired nucleic-acid disposal - into type I interferon, NF-kB, autophagy-related, and senescence-associated inflammatory programs. Rather than treating cGAS-STING as a universal disease-defining pathway, this review frames it as a context-dependent amplifier that becomes pathogenic when DNA-DAMP burden, defective mitochondrial quality control, neurovascular “leakage”, and glial priming converge. We synthesize cell-type-specific evidence in microglia, astrocytes, neurons, and the neurovascular unit; compare mechanistic involvement across Alzheimer’s disease, Parkinson’s disease dementia and Lewy body disease, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), vascular and acute brain injury, and systemic inflammatory encephalopathies; and organize periphery-to-brain communication axes using an explicit evidence-grading framework. A distinctive contribution of this review is a two-hit model in which systemic inflammatory stressors and barrier dysfunction first lower cognitive resilience, followed by brain-resident mitochondrial/DNA damage programs that lock in complement-linked synaptopathy. We also evaluate pharmacological and lifestyle-based modulation, emphasizing biomarker-enriched trial design, CNS exposure, compartment-specific target engagement, and immune-safety constraints. This framework aims to clarify when, where, and in whom cGAS-STING modulation may preserve synapses and cognition without unacceptable immune trade-offs.
Graphical Abstract: cGAS-STING couples self-DNA sensing to neuroinflammation and cognitive decline. Self-DNA released during mitochondrial dysfunction or micronuclear rupture is sensed by cGAS to generate the second messenger cGAMP, which activates STING and drives type I interferon (IFN-I) and pro-inflammatory cytokine programs. Sustained signaling amplifies synaptic elimination and neuronal dysfunction, linking diverse upstream stressors to cognitive decline.
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BibTeX
@article{wu2026cgassting,
title = {{The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication}},
author = {Yuming Wu and Xue Zhang and Chenggang Gao and Zheng Zhang and Xuelian Liao and Yan Kang},
journal = {Cellular and Molecular Neurobiology},
year = {2026},
month = jul,
doi = {10.1007/s10571-026-01786-8},
url = {https://doi.org/10.1007/s10571-026-01786-8},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication
AU - Yuming Wu
AU - Xue Zhang
AU - Chenggang Gao
AU - Zheng Zhang
AU - Xuelian Liao
AU - Yan Kang
PY - 2026
DA - 2026/07/31
JO - Cellular and Molecular Neurobiology
DO - 10.1007/s10571-026-01786-8
UR - https://doi.org/10.1007/s10571-026-01786-8
AB - Neurodegenerative disorders involve a strong inflammatory component, yet the underlying inflammatory mechanisms may be heterogeneous across disease stage, cell type, and systemic context. A key unresolved question is how cellular and systemic stress is converted into sustained neuroinflammation. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate DNA-sensing hub that translates mislocalized self-DNA - derived from mitochondrial stress and mtDNA leakage, nuclear envelope instability, micronuclei formation, or impaired nucleic-acid disposal - into type I interferon, NF-kB, autophagy-related, and senescence-associated inflammatory programs. Rather than treating cGAS-STING as a universal disease-defining pathway, this review frames it as a context-dependent amplifier that becomes pathogenic when DNA-DAMP burden, defective mitochondrial quality control, neurovascular “leakage”, and glial priming converge. We synthesize cell-type-specific evidence in microglia, astrocytes, neurons, and the neurovascular unit; compare mechanistic involvement across Alzheimer’s disease, Parkinson’s disease dementia and Lewy body disease, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), vascular and acute brain injury, and systemic inflammatory encephalopathies; and organize periphery-to-brain communication axes using an explicit evidence-grading framework. A distinctive contribution of this review is a two-hit model in which systemic inflammatory stressors and barrier dysfunction first lower cognitive resilience, followed by brain-resident mitochondrial/DNA damage programs that lock in complement-linked synaptopathy. We also evaluate pharmacological and lifestyle-based modulation, emphasizing biomarker-enriched trial design, CNS exposure, compartment-specific target engagement, and immune-safety constraints. This framework aims to clarify when, where, and in whom cGAS-STING modulation may preserve synapses and cognition without unacceptable immune trade-offs. Graphical Abstract: cGAS-STING couples self-DNA sensing to neuroinflammation and cognitive decline. Self-DNA released during mitochondrial dysfunction or micronuclear rupture is sensed by cGAS to generate the second messenger cGAMP, which activates STING and drives type I interferon (IFN-I) and pro-inflammatory cytokine programs. Sustained signaling amplifies synaptic elimination and neuronal dysfunction, linking diverse upstream stressors to cognitive decline.
SN - 0272-4340
SN - 1573-6830
ER -