HDAC3 inhibition alleviates neuroinflammation and white matter injury after subarachnoid hemorrhage through modulation of BDNF/TrkB/NF-κB signaling

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.