Lysine β-hydroxybutyrylation in metabolic plasticity and disease pathogenesis.

Lysine β-hydroxybutyrylation (Kbhb) represents a novel post-translational modification (PTM) mediated by ketone body metabolites, particularly β-hydroxybutyric acid (BHB). This modification exhibits dynamic elevation under ketogenic conditions including diabetic ketoacidosis, neonatal metabolic disorders, fasting, and sustained physical exertion, where circulating BHB concentrations exceed physiological thresholds. Emerging evidence positions Kbhb as a critical epigenetic-metabolic interface, with demonstrated regulatory roles spanning oncology, immunomodulation, cardiovascular homeostasis, neuropsychiatric disorders, circadian biology, and developmental processes. Mechanistically, Kbhb affects metabolic plasticity through modulating structural modification of key metabolic enzyme as well as metabolic flux. In addition, Kbhb exerts pleiotropic effects via competitive interplay with canonical PTMs (acetylation, methylation) at critical lysine residues. Kbhb-induced epigenomic reorganization through enhancer/promoter domain enrichment facilitates transcriptional activation of functional gene and mediates transcriptional network during the progression of multiple diseases. This review systematically examines the discovery timeline, enzymatic machinery governing Kbhb dynamics (writers/erasers/readers), molecular mechanisms underlying its pathophysiological functions, and therapeutic implications across disease states. The elucidation of Kbhb-induced metabolic signaling paradigms and other molecular interfaces catalyzes the development of innovative therapeutic strategies across multiple diseases.