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Updated: Dec 10, 2025
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Published on: January 10, 2025
HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING
Yajin Liao1,2, Jinbo Cheng1,2, Xiangxi Kong1
1The Brain Science Center, Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Haidian District, Beijing 100850, China.
Insights
Histone deacetylase 3 (HDAC3) regulates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in microglia, mitigating neuroinflammation and brain injury following cerebral ischemia/reperfusion (I/R). This identifies a new therapeutic target for ischemic stroke.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Neuroinflammation critically contributes to cerebral ischemia/reperfusion (I/R) injury.
- The role of the cyclic GMP-AMP synthase (cGAS)-mediated innate immune response in I/R-induced neuroinflammation remains largely uncharacterized.
Purpose of the Study:
- To investigate the function and regulatory mechanism of cGAS in I/R-induced neuroinflammation and brain injury.
- To identify potential therapeutic strategies for ischemic stroke by exploring the cGAS pathway.
Main Methods:
- Utilized transient middle cerebral artery occlusion (tMCAO) model in rodents.
- Employed molecular and biochemical techniques including RNA sequencing, western blot, co-immunoprecipitation, and immunohistochemistry.
- Assessed microglial activation of the cGAS-STING pathway and the role of histone deacetylase 3 (HDAC3).
Main Results:
- Microglial cGAS-STING pathway activation by mitochondrial DNA promotes a pro-inflammatory environment.
- HDAC3 enhances cGAS expression and cGAS-STING pathway activation by regulating p65 acetylation and nuclear localization in microglia.
- Genetic deletion of cGAS or HDAC3 in microglia significantly reduced I/R-induced neuroinflammation and brain injury.
Conclusions:
- The HDAC3-p65-cGAS-STING pathway is implicated in the pathogenesis of I/R-induced neuroinflammation.
- This pathway represents a novel therapeutic target for treating ischemic stroke.
Abstract:
Rationale: It is known that neuroinflammation plays a critical and detrimental role in the development of cerebral ischemia/reperfusion (I/R), but the regulation of the cyclic GMP-AMP synthase (cGAS)-mediated innate immune response in I/R-induced neuroinflammation is largely unexplored. This study aimed to investigate the function and regulatory mechanism of cGAS in I/R-induced neuroinflammation and brain injury, and to identify possible strategies for the treatment of ischemic stroke. Methods: To demonstrate that microglial histone deacetylase 3 (HDAC3) regulates the microglial cGAS-stimulator of interferon genes (cGAS-STING) pathway and is involved in I/R-induced neuroinflammation and brain injury, a series of cell biological, molecular, and biochemical approaches were utilized. These approaches include transient middle cerebral artery occlusion (tMCAO), real-time polymerase chain reaction (PCR), RNA sequencing, western blot, co-immunoprecipitation, chromosome-immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), dual-luciferase reporter assay, immunohistochemistry, and confocal imaging. Results: The microglial cGAS- STING pathway was activated by mitochondrial DNA, which promoted the formation of a pro-inflammatory microenvironment. In addition, we revealed that HDAC3 transcriptionally promoted the expression of cGAS and potentiated the activation of the cGAS-STING pathway by regulating the acetylation and nuclear localization of p65 in microglia. Our in vivo results indicated that deletion of cGAS or HDAC3 in microglia attenuated I/R-induced neuroinflammation and brain injury. Conclusion: Collectively, we elucidated that the HDAC3-p65-cGAS-STING pathway is involved in the development of I/R-induced neuroinflammation, identifying a new therapeutic avenue for the treatment of ischemic stroke.
