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Peer-reviewedCC BYJournal of Clinical Investigation

Expanding roles of cGAS-STING signaling in neuroinflammation

  • Weixi Feng1
  • Abulimiti Aikedan1,2
  • Subhash C. Sinha1
  • Li Gan1
  1. 1Helen and Robert Appel Alzheimer Disease Research Institute, Feil Family Brain and Mind Research Institute, and
  2. 2Physiology, Biophysics and Systems Biology graduate program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, New York, USA
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Abstract

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central mediator of cytosolic DNA-induced innate immune responses, driving the production of type I IFNs and pro-inflammatory cytokines. Beyond its canonical role in cytosolic DNA sensing, increasing attention has been directed toward the noncanonical functions of cGAS and STING, particularly within the nucleus. Recent studies implicate dysregulated cGAS-STING signaling in neurodegenerative diseases and brain aging, with a prominent contribution to glial activation-associated neuroinflammation, a hallmark of many neurological disorders. In this Review, we first summarize the molecular mechanisms underlying the canonical cGAS-STING pathway in DNA sensing and innate immune activation. We then discuss emerging noncanonical roles of cGAS in chromatin organization and RNA metabolism, drawing on insights from evolutionary conservation and protein interactome analyses. Finally, we outline the involvement of cGAS-STING signaling in diverse aspects of brain function, including glial state regulation, neuronal homeostasis, blood-brain barrier integrity, and peripheral immune surveillance, highlighting their contributions to neuroinflammation and neuropathology. We also summarize current pharmacological inhibitors targeting cGAS and STING and discuss their therapeutic potential for modulating cGAS-STING signaling to manage brain disorders.

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Cite

BibTeXRIS
BibTeX
@article{feng2026expanding,
  title = {{Expanding roles of cGAS-STING signaling in neuroinflammation}},
  author = {Weixi Feng and Abulimiti Aikedan and Subhash C. Sinha and Li Gan},
  journal = {Journal of Clinical Investigation},
  year = {2026},
  month = jun,
  doi = {10.1172/jci204550},
  url = {https://doi.org/10.1172/jci204550},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Expanding roles of cGAS-STING signaling in neuroinflammation
AU  - Weixi Feng
AU  - Abulimiti Aikedan
AU  - Subhash C. Sinha
AU  - Li Gan
PY  - 2026
DA  - 2026/06/01
JO  - Journal of Clinical Investigation
DO  - 10.1172/jci204550
UR  - https://doi.org/10.1172/jci204550
AB  - The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central mediator of cytosolic DNA-induced innate immune responses, driving the production of type I IFNs and pro-inflammatory cytokines. Beyond its canonical role in cytosolic DNA sensing, increasing attention has been directed toward the noncanonical functions of cGAS and STING, particularly within the nucleus. Recent studies implicate dysregulated cGAS-STING signaling in neurodegenerative diseases and brain aging, with a prominent contribution to glial activation-associated neuroinflammation, a hallmark of many neurological disorders. In this Review, we first summarize the molecular mechanisms underlying the canonical cGAS-STING pathway in DNA sensing and innate immune activation. We then discuss emerging noncanonical roles of cGAS in chromatin organization and RNA metabolism, drawing on insights from evolutionary conservation and protein interactome analyses. Finally, we outline the involvement of cGAS-STING signaling in diverse aspects of brain function, including glial state regulation, neuronal homeostasis, blood-brain barrier integrity, and peripheral immune surveillance, highlighting their contributions to neuroinflammation and neuropathology. We also summarize current pharmacological inhibitors targeting cGAS and STING and discuss their therapeutic potential for modulating cGAS-STING signaling to manage brain disorders.
SN  - 0021-9738
SN  - 1558-8238
ER  -