β-hydroxybutyrate alleviates depressive behaviors in mice possibly by increasing the histone3-lysine9-β-hydroxybutyrylation.

Epigenetics regulation has been considered a mechanistic interface between environmental stress stimuli and altered functioning of underlying gene network. Metabolite changes in vivo after stress contribute to histone modification. Histone3-lysine9-β-hydroxybutyrylation (H3k9bhb), a novel histone modification mark induced by β-hydroxybutyrate, may participate in the development of depression. To examine the role of H3k9bhb in depression, experiments were performed on mice and cells. H3k9bhb were reduced in the brain of depressive mice. Exogenous β-hydroxybutyrate ameliorated depressive behaviors and reversed the reduction of H3K9bhb and BDNF. We showed that H3k9bhb played a role in depression, and firstly linked BHB and BDNF via H3k9bhb. Our findings emphasized the crucial role of metabolic regulation on epigenetics in depression.