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Abstract The metabolic switch from oxidative phosphorylation to glycolysis is a vital hallmark and prerequisite for microglia phenotype transition. Recently, histone lactylation was shown to promote macrophage homeostatic gene expression via transcriptional regulation. However, the role of histone lactylation in regulating microglia function in Parkinson’s disease (PD) remains unclear. Here, we show that glycolytic inhibitor 2-deoxy-D-glucose alleviatesmicrogliosis, neuroinflammation, and dopaminergic neuronal damage by reducing lactate accumulation. Notably, histone lactylation, especially H3K9la, is markedly increased in microglia within the substantia nigra of a mouse model of PD and lipopolysaccharide-stimulated primary microglia. Mechanistically, enhanced glycolysis-derived lactate induces H3K9la enrichment at the promoter of solute carrier family 7 member 11 (Slc7a11), promoting its transcription. Inhibition ofSLC7A11 by sulfasalazine mitigates microglia-mediated neuroinflammation and improves motor function in the mouse model PD mice. Moreover, lactate-induced histone lactylation is dependent on the p300/CBP. Collectively, ourfindings demonstrate that augmented glycolysis-derived lactate promotes microglial activation via histone lactylation and provide a novel therapeutic strategy for PD.
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