{
  "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.\n\nGraphical 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan China",
    "Department of Critical Care Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, Sichuan China"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yuming Wu",
      "orcid": "0000-0003-4663-3762"
    },
    {
      "affs": [
        0
      ],
      "name": "Xue Zhang",
      "orcid": "0000-0002-8874-5108"
    },
    {
      "affs": [
        0
      ],
      "name": "Chenggang Gao",
      "orcid": "0000-0003-4939-1519"
    },
    {
      "affs": [
        0
      ],
      "name": "Zheng Zhang",
      "orcid": "0009-0009-7006-1347"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xuelian Liao",
      "orcid": "0000-0002-9121-0761"
    },
    {
      "affs": [
        0
      ],
      "name": "Yan Kang",
      "orcid": "0000-0002-5715-3900"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5gc83gjmxq26y.bib",
  "cited_by": 0,
  "doi": "10.1007/s10571-026-01786-8",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13710525/",
  "id": "5gc83gjmxq26y",
  "issns": [
    "0272-4340",
    "1573-6830"
  ],
  "landing_url": "https://doi.org/10.1007/s10571-026-01786-8",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Review Paper"
    ],
    [
      "openalex",
      "2808|Neuroinflammation and Neurodegeneration Mechanisms"
    ]
  ],
  "openalex": "W7171843538",
  "pdf_url": null,
  "pmcid": "PMC13710525",
  "pmid": "42934377",
  "published": "2026-07-31",
  "publisher": "Springer",
  "ris": "https://research.draconitic.com/paper/5gc83gjmxq26y.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:21:28Z",
      "native_id": "PMC13710525",
      "source": "pmc",
      "url": "https://doi.org/10.1007/s10571-026-01786-8"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2808|Neuroinflammation and Neurodegeneration Mechanisms",
      "subfield": "neurology"
    }
  ],
  "title": "The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication",
  "title_text": "The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:21:28Z",
  "url": "https://research.draconitic.com/paper/5gc83gjmxq26y",
  "venue": "Cellular and Molecular Neurobiology",
  "versions": []
}