HDAC3 inhibition alleviates neuroinflammation and white matter injury after subarachnoid hemorrhage through modulation of BDNF/TrkB/NF-κB signaling
- 1Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 315010, China
- 2Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- 3Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 315010, China; Corresponding author.
Abstract
White matter injury (WMI) is a major contributor to neurological deficits after subarachnoid hemorrhage (SAH). Histone deacetylase 3 (HDAC3) is an established modulator of inflammatory responses, yet its contribution to post-SAH white matter pathology remains poorly understood. We used a rat endovascular perforation model and treated animals with RGFP966, a selective HDAC3 inhibitor. Clinical data, single-cell RNA sequencing (scRNA-seq), magnetic resonance imaging (MRI), and transmission electron microscopy were integrated to evaluate cellular remodeling and structural integrity. Short- and long-term neurological recovery was assessed using a systematic battery of behavioral tests, while the underlying BDNF/TrkB/NF-κB signaling axis was validated through gain- and loss-of-function experiments. HDAC3 levels were elevated in both the CSF of SAH patients and rat brain tissues, inversely correlating with myelin basic protein (MBP) expression. RGFP966 treatment effectively preserved WMI, evidenced by reduced axonal injury and improved myelin shielding, and translated to superior long-term cognitive performance. ScRNA-seq analysis identified a profound shift in the microglial and oligodendrocyte-lineage landscapes after SAH. HDAC3 inhibition effectively curbed the expansion of pro-inflammatory microglial subsets while restoring homeostatic signatures and enhancing pro-myelination programs. Mechanistically, RGFP966 upregulated BDNF expression and restored TrkB phosphorylation, thereby suppressing NF-κB-mediated neuroinflammation. Notably, BDNF knockdown abolished the protective effects of HDAC3 inhibition, whereas exogenous BDNF mimicked the anti-inflammatory and myelin-protective phenotype induced by RGFP966. In conclusion, our findings demonstrate that HDAC3 is a pivotal driver of post-SAH neuroinflammation and WMI. Inhibition of HDAC3 exerts neuroprotection by recalibrating the microglial immune microenvironment and restoring the BDNF/TrkB axis.
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BibTeX
@article{yang2026hdac3,
title = {{HDAC3 inhibition alleviates neuroinflammation and white matter injury after subarachnoid hemorrhage through modulation of BDNF/TrkB/NF-κB signaling}},
author = {Hongqiao Yang and Ziliang Hu and Hao Zhuang and Siqi Chen and Shengjun Zhou and Meng Sun and Lifei Lian and Chenhui Zhou and Xiang Gao and Yi Huang},
journal = {Neurotherapeutics},
year = {2026},
month = oct,
doi = {10.1016/j.neurot.2026.e01099},
url = {https://doi.org/10.1016/j.neurot.2026.e01099},
note = {CC BY},
}
RIS
TY - JOUR
TI - HDAC3 inhibition alleviates neuroinflammation and white matter injury after subarachnoid hemorrhage through modulation of BDNF/TrkB/NF-κB signaling
AU - Hongqiao Yang
AU - Ziliang Hu
AU - Hao Zhuang
AU - Siqi Chen
AU - Shengjun Zhou
AU - Meng Sun
AU - Lifei Lian
AU - Chenhui Zhou
AU - Xiang Gao
AU - Yi Huang
PY - 2026
DA - 2026/10/31
JO - Neurotherapeutics
DO - 10.1016/j.neurot.2026.e01099
UR - https://doi.org/10.1016/j.neurot.2026.e01099
AB - White matter injury (WMI) is a major contributor to neurological deficits after subarachnoid hemorrhage (SAH). Histone deacetylase 3 (HDAC3) is an established modulator of inflammatory responses, yet its contribution to post-SAH white matter pathology remains poorly understood. We used a rat endovascular perforation model and treated animals with RGFP966, a selective HDAC3 inhibitor. Clinical data, single-cell RNA sequencing (scRNA-seq), magnetic resonance imaging (MRI), and transmission electron microscopy were integrated to evaluate cellular remodeling and structural integrity. Short- and long-term neurological recovery was assessed using a systematic battery of behavioral tests, while the underlying BDNF/TrkB/NF-κB signaling axis was validated through gain- and loss-of-function experiments. HDAC3 levels were elevated in both the CSF of SAH patients and rat brain tissues, inversely correlating with myelin basic protein (MBP) expression. RGFP966 treatment effectively preserved WMI, evidenced by reduced axonal injury and improved myelin shielding, and translated to superior long-term cognitive performance. ScRNA-seq analysis identified a profound shift in the microglial and oligodendrocyte-lineage landscapes after SAH. HDAC3 inhibition effectively curbed the expansion of pro-inflammatory microglial subsets while restoring homeostatic signatures and enhancing pro-myelination programs. Mechanistically, RGFP966 upregulated BDNF expression and restored TrkB phosphorylation, thereby suppressing NF-κB-mediated neuroinflammation. Notably, BDNF knockdown abolished the protective effects of HDAC3 inhibition, whereas exogenous BDNF mimicked the anti-inflammatory and myelin-protective phenotype induced by RGFP966. In conclusion, our findings demonstrate that HDAC3 is a pivotal driver of post-SAH neuroinflammation and WMI. Inhibition of HDAC3 exerts neuroprotection by recalibrating the microglial immune microenvironment and restoring the BDNF/TrkB axis.
SN - 1878-7479
SN - 1933-7213
ER -