Metabolism Meets Epigenetics: β-Hydroxybutyrate–Driven Lysine β-Hydroxybutyrylation Bridging Energy Metabolism With Transcription and Protein Functional Remodeling

Abstract β-Hydroxybutyrate (BHB) is the primary product of ketone body metabolism. Beyond serving as an energy source, BHB plays a crucial role in metabolic regulation, anti-inflammatory and antioxidative responses, immune modulation, and neuroprotection. Circulating BHB levels are closely linked to dietary composition and lifestyle. Medium-chain fatty acids, fasting, ketogenic diets, and moderate exercise promote BHB production, and exogenous ketone supplements can rapidly elevate BHB without the need for carbohydrate restriction. Studies have shown that BHB can regulate gene expression through epigenetic modifications, with lysine β-hydroxybutyrylation (Kbhb) establishing a crucial link between ketone body metabolism and gene regulation. Kbhb modulates chromatin accessibility, gene transcription, and cellular metabolism, and its substrates extend beyond histones to include non-histone proteins. Consequently, this modification is essential for maintaining physiological homeostasis and regulating disease processes. Despite substantial progress in Kbhb research, its precise regulatory mechanisms remain incompletely understood. Histone deacetylases (HDACs) and the sirtuin (SIRT) family function as “erasers” (enzymes that catalyze the removal of specific post-translational modifications from histone and non-histone proteins), whereas E1A-binding protein p300 and its homolog CREB-binding protein (p300/CBP) act as “writers” (enzymes that catalyze the addition of specific post-translational modifications to histone and non-histone proteins), both playing pivotal roles in the dynamic regulation of Kbhb modification. This review summarizes the biological functions of BHB and Kbhb, emphasizing their roles in metabolic regulation, their nutritional connections, epigenetic modifications, and disease development.