β-Hydroxybutyrate (βOHB), an endogenous ketone body, is a specific inhibitor of class I histone deacetylases (HDACs). The study shows that βOHB increases global histone acetylation in mouse tissues, which is associated with increased transcription of genes involved in oxidative stress resistance, such as FOXO3A and MT2. βOHB inhibits HDAC1, HDAC3, and HDAC4 in a dose-dependent manner, while it does not inhibit HDAC6. This inhibition leads to increased histone acetylation at the promoters of FOXO3A and MT2, activating these genes. βOHB treatment in mice conferred protection against oxidative stress, as evidenced by reduced protein carbonylation and lipid peroxidation. The study also found that βOHB increases histone acetylation in the kidney, which is correlated with increased βOHB concentrations in the serum. The findings suggest that βOHB acts as an endogenous HDAC inhibitor, linking metabolic status with epigenetic changes. This mechanism may contribute to the protective effects of calorie restriction and ketogenic diets against oxidative stress.β-Hydroxybutyrate (βOHB), an endogenous ketone body, is a specific inhibitor of class I histone deacetylases (HDACs). The study shows that βOHB increases global histone acetylation in mouse tissues, which is associated with increased transcription of genes involved in oxidative stress resistance, such as FOXO3A and MT2. βOHB inhibits HDAC1, HDAC3, and HDAC4 in a dose-dependent manner, while it does not inhibit HDAC6. This inhibition leads to increased histone acetylation at the promoters of FOXO3A and MT2, activating these genes. βOHB treatment in mice conferred protection against oxidative stress, as evidenced by reduced protein carbonylation and lipid peroxidation. The study also found that βOHB increases histone acetylation in the kidney, which is correlated with increased βOHB concentrations in the serum. The findings suggest that βOHB acts as an endogenous HDAC inhibitor, linking metabolic status with epigenetic changes. This mechanism may contribute to the protective effects of calorie restriction and ketogenic diets against oxidative stress.