In cell and mouse models of Parkinson's disease, HDAC3 inhibition reduced microglial M1 polarization and proinflammatory cytokine production, suppressed pyroptosis via an interaction with HIF‑1α, and preserved nigral dopaminergic neurons with improved behavior.

Pins HDAC3 as an actionable anti‑inflammatory/anti‑pyroptotic target with in vivo neuroprotection, supporting further preclinical development or repurposing of selective HDAC3 inhibitors for PD therapeutics.

Neuroinflammation, mediated by microglial cells, plays a crucial role in the progression of Parkinson's disease. Although the importance of histone deacetylase 3 in neurodegenerative diseases is well recognized, its specific involvement in microglial cells in the context of Parkinson's disease pathogenesis remains unclear. By analyzing gene expression data from the Gene Expression Omnibus database, we identified the potential role of histone deacetylase 3 in Parkinson's disease. We found a significant increase of histone deacetylase 3 in lipopolysaccharide-stimulated BV2 cells and substantia nigra microglial cells of Parkinson's disease model mice. Inhibition of histone deacetylase 3 was found to lead to a notable reduction in the production of proinflammatory factors and promote the transformation of microglial cells from a pro-inflammatory M1 phenotype into an anti-inflammatory M2 phenotype. In addition, histone deacetylase 3 inhibition exerts a neuroprotective effect on co-cultured dopamine neurons in lipopolysaccharide-stimulated BV2 cells. Crucially, the inhibition of histone deacetylase 3 in the in vivo Parkinson's disease model led to enhanced behavioral recovery and halted dopaminergic neuron degeneration in mice. To further investigate the mechanisms underlying this role of histone deacetylase 3, we employed Ingenuity Pathway Analysis software to elucidate the interaction between histone deacetylase 3 and hypoxia-inducible factor 1-alpha. Our study demonstrates that histone deacetylase 3 blockade effectively suppresses the inflammation and M1 polarization of lipopolysaccharide-stimulated microglia. Furthermore, it inhibits pyroptosis through interaction with hypoxia-inducible factor 1-alpha to prevent dopaminergic neuron death. These findings suggest that targeting histone deacetylase 3 could represent a promising therapeutic strategy for Parkinson's disease.