The study investigates the effects of β-hydroxybutyrate (βOHB), a ketone body, on histone deacetylases (HDACs) and oxidative stress resistance. βOHB is found to be an endogenous and specific inhibitor of class I HDACs, increasing global histone acetylation in mouse tissues. This increase in acetylation is correlated with changes in gene expression, particularly in genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment with βOHB enhances histone acetylation at the Foxo3a and Mt2 promoters, leading to their activation. In mice, βOHB treatment confers significant protection against oxidative stress, as evidenced by reduced protein carbonylation and lipid peroxidation. The findings suggest that βOHB's effects on HDAC inhibition and histone acetylation contribute to its protective role against oxidative stress.The study investigates the effects of β-hydroxybutyrate (βOHB), a ketone body, on histone deacetylases (HDACs) and oxidative stress resistance. βOHB is found to be an endogenous and specific inhibitor of class I HDACs, increasing global histone acetylation in mouse tissues. This increase in acetylation is correlated with changes in gene expression, particularly in genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment with βOHB enhances histone acetylation at the Foxo3a and Mt2 promoters, leading to their activation. In mice, βOHB treatment confers significant protection against oxidative stress, as evidenced by reduced protein carbonylation and lipid peroxidation. The findings suggest that βOHB's effects on HDAC inhibition and histone acetylation contribute to its protective role against oxidative stress.