Targeting the cGAS-STING axis in Alzheimer’s disease: neuroinflammation-centric therapeutic strategies and perspectives
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder traditionally characterized by amyloid-β (Aβ) plaques and tau neurofibrillary tangles. However, the limited clinical efficacy of Aβ/tau-targeted therapies has redefined neuroinflammation as an active driver of AD pathogenesis. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis acts as a central hub connecting aberrant cytosolic nucleic acid sensing particularly mitochondrial DNA leakage induced by Aβ and tau pathologies to chronic innate immune activation. This review comprehensively elucidates the pathogenic mechanisms of the cGAS-STING axis in AD, detailing its cell-type-specific activation in microglia, astrocytes, and neurons, and its downstream propagation via type I interferons, NF-κB, and NLRP3 inflammasome signaling, which collectively drive synaptic damage and neuronal loss. We critically evaluate emerging therapeutic strategies, including covalent/non-covalent small-molecule inhibitors (e.g., RU.521, H-151, PF-06928215, SN-011), PROTAC degraders, RNA-based therapies, and immunomodulatory natural products/traditional Chinese medicines (e.g., icariin, tetrahydroxy stilbene glucoside, compound danshen dripping pills). Furthermore, we explore clinical translation prospects, emphasizing cerebrospinal fluid cGAMP and exosomal phosphorylated STING as minimally invasive biomarkers, while addressing key hurdles in blood-brain barrier penetration, and off-target risks. Finally, we highlight future directions involving organoid-microfluidic chip models and precision medicine frameworks to facilitate personalized cGAS-STING-targeted immunotherapy for AD.
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BibTeX
@article{liu2026targeting,
title = {{Targeting the cGAS-STING axis in Alzheimer’s disease: neuroinflammation-centric therapeutic strategies and perspectives}},
author = {Jiayi Liu and Xiaoqin Shan and Siyi Li and Xianping Li and Can Wang and Lili Gu and Xinyue Zhang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.1983598},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1983598},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting the cGAS-STING axis in Alzheimer’s disease: neuroinflammation-centric therapeutic strategies and perspectives
AU - Jiayi Liu
AU - Xiaoqin Shan
AU - Siyi Li
AU - Xianping Li
AU - Can Wang
AU - Lili Gu
AU - Xinyue Zhang
PY - 2026
DA - 2026/11/03
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1983598
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1983598
AB - Alzheimer’s disease (AD) is a progressive neurodegenerative disorder traditionally characterized by amyloid-β (Aβ) plaques and tau neurofibrillary tangles. However, the limited clinical efficacy of Aβ/tau-targeted therapies has redefined neuroinflammation as an active driver of AD pathogenesis. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis acts as a central hub connecting aberrant cytosolic nucleic acid sensing particularly mitochondrial DNA leakage induced by Aβ and tau pathologies to chronic innate immune activation. This review comprehensively elucidates the pathogenic mechanisms of the cGAS-STING axis in AD, detailing its cell-type-specific activation in microglia, astrocytes, and neurons, and its downstream propagation via type I interferons, NF-κB, and NLRP3 inflammasome signaling, which collectively drive synaptic damage and neuronal loss. We critically evaluate emerging therapeutic strategies, including covalent/non-covalent small-molecule inhibitors (e.g., RU.521, H-151, PF-06928215, SN-011), PROTAC degraders, RNA-based therapies, and immunomodulatory natural products/traditional Chinese medicines (e.g., icariin, tetrahydroxy stilbene glucoside, compound danshen dripping pills). Furthermore, we explore clinical translation prospects, emphasizing cerebrospinal fluid cGAMP and exosomal phosphorylated STING as minimally invasive biomarkers, while addressing key hurdles in blood-brain barrier penetration, and off-target risks. Finally, we highlight future directions involving organoid-microfluidic chip models and precision medicine frameworks to facilitate personalized cGAS-STING-targeted immunotherapy for AD.
SN - 1663-9812
ER -