Huntington's disease (HD) is a genetic neurodegenerative disease that damages primarily the striatum and leads to motor, cognitive and psychiatric symptoms. The HD striatum undergoes early specific epigenetic gene reprogramming, leading to progressive impairment of striatal neuron identity and function. Notably, genes that define striatal neuron identity are progressively down-regulated due to decreased histone acetylation (e.g. H3K27 acetylation -H3K27ac-). Additionally, developmental genes show an increase in H3K27ac, leading to their derepression. Histone acetylation is strongly connected to energy metabolism through acetyl-CoA, the only donor of acetyl group for histone acetylation. Additional acyl-CoAs can also modify histones, so-called histone acylome, including lactyl-CoA, crotonyl-CoA …, leading to histone lactylation, histone crotonylation, … thereby helping adjusting gene expression program to metabolic status. Energy metabolism, including acyl-CoA metabolism, is early impaired in the HD striatum, which might drive general impairment of the histone acylome and subsequent gene expression reprogramming. To explore the hypothesis, we perform broad characterization of the HD striatal histone acylome, using HD mouse models and ChIPseq/CUT&Tag epigenomic and histone proteomic approaches. Our data indicate that histone acetylation is generally impaired and also suggest that histone lactylation (e.g. H3K18 lactylation) is dysregulated in the striatum of HD mice. Together, these data are consistent with a scenario where broad impairment of the histone acylome in the HD striatum results from energy metabolism imbalance, and triggers transcriptional dysregulation.