Recently, Huang et al. found that acetate supplementation (a major source of acetyl coenzyme A) significantly improved depression-like behaviors in mice, substantially reduced transcript levels of HDAC2, HDAC5, HDAC7, and HDAC8, increased transcript levels of HAT and P300, and enhanced nuclear acetyl coenzyme A content, promoting acetylation levels of histones H3 and H4 (Huang et al., 2021), suggesting that acetate might exert antidepressant-like effects by enhancing acetylation of certain histones. This evidence concerns the gene EP300 and major depressive disorder.