Fig. 1.

The BHB regulates epigenetics.

Ketogenic diets (KD), alternate-day fasting (ADF), time-restricted feeding (TRF), fasting, diabetic ketoacidosis (DKA), and SGLT-2 inhibitors cause an increase in BHB concentration. BHB metabolism in mitochondrion increases Ac-CoA, which is transported to the nucleus as a substrate for histone acetyltransferase (HAT) and promotes Kac. BHB also directly inhibits histone deacetylase (HDAC) and then increases Kac. However, excessive NAD⁺ during BHB metabolism activates Sirtuin and reduces Kac. BHB may be catalyzed by acyl-CoA synthetase 2 (ACSS2) to produce BHB-CoA and promote Kbhb under acyltransferase P300. BHB directly promotes Kme via cAMP/PKA signaling but indirectly inhibits Kme by enhancing the expression of histone demethylase JMJD3. BHB blocks DNA methylation by inhibiting DNA methyltransferase (DNMT). Furthermore, BHB also up-regulates microRNAs and affects gene expression. These BHB-regulated epigenetic effects are involved in the regulation of oxidative stress, inflammation, fibrosis, tumors, and neurobiological-related signaling. The “dotted lines” mean that the process needs to be further verified, and the solid lines mean that the process has been proven.