IMR Press / JIN / Volume 22 / Issue 6 / DOI: 10.31083/j.jin2206156
Open Access Original Research
HDAC3 Contributes to Ischemic Stroke by Regulating Interferon Pathway
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1 Department of Anesthesiology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001 Hefei, Anhui, China
2 School of Medicine, Xiamen University, 361000 Xiamen, Fujian, China
3 Department of Neurology, The 904th Hospital of PLA, Medical School of Anhui Medical University, 214000 Wuxi, Jiangsu, China
4 Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, 361000 Xiamen, Fujian, China
*Correspondence: (Hongrui Zhu); (Sheng Wang)
These authors contributed equally.
J. Integr. Neurosci. 2023, 22(6), 156;
Submitted: 17 February 2023 | Revised: 31 March 2023 | Accepted: 7 April 2023 | Published: 30 October 2023
(This article belongs to the Special Issue Neuroprotection in Stroke)
Copyright: © 2023 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: The inflammation and immune response contribute to ischemic stroke pathology. Damaged brain cells release inflammatory substances to activate the immune system in the acute phase of stroke, including altering the interferon signaling pathway. However, the involvement of histone deacetylation in stroke remains unclear. Methods: To investigate whether histone deacetylation modulation could regulate the interferon signaling pathway and mediate the pathogenic changes after stroke, the middle cerebral artery occlusion (MCAO) mouse model was treated with histone deacetylase 3 (HDAC3) inhibitor and RGFP966. Additionally, a series of approaches, including middle cerebral artery occlusion (MCAO), real-time polymerase chain reaction (PCR), western blot, 2,3,5-triphenyltetrazolium chloride (TTC) staining, behavioral experiments, and confocal imaging were utilized. Results: It is observed that RGFP966 pretreatment could lead to better outcomes in the MCAO mouse model, including the decrease of infarction volumes, the amelioration of post-stroke anxiety-like behavior, and the relief of inflammatory responses. Furthermore, we found that RGFP966 could counteract the hyperactivation of the interferon signaling pathway and the excessive expression of Z-DNA Binding Protein 1 (ZBP1) in microglia. Conclusions: We demonstrated a novel mechanism that HDAC3 inhibition could ameliorate the pathological injury after ischemic stroke by downregulating the ZBP1/phosphorylated Interferon Regulatory Factor 3 (p-IRF3) pathway. Thus, these data provide a new promising target for therapies for ischemic stroke.

ischemic stroke
histone deacetylase 3
Z-DNA binding protein 1
phosphorylated Interferon Regulatory Factor 3
82272225/National Natural Science Foundation of China
81860249/National Natural Science Foundation of China
Fig. 1.
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