Lysine β-hydroxybutyrylation: A metabolic-epigenetic interface in health and disease

Lysine β-hydroxybutyrylation (Kbhb) is a β-hydroxybutyrate-derived lysine acylation that connects ketone-body metabolism with chromatin regulation and non-histone protein function. Initially described as a fasting-responsive histone mark, Kbhb is now implicated in immune memory, metabolic adaptation, cancer metabolism and neuroprotection.

This Review reframes Kbhb as a context-dependent metabolic acylation system. We discuss the metabolic origin of β-hydroxybutyryl-CoA, the writer, reader and eraser machinery of Kbhb, its crosstalk with acetylation, lactylation and crotonylation, and the evidence standards required to distinguish Kbhb-driven mechanisms from broader β-hydroxybutyrate biology.

Recent studies have identified p300/CBP as a Kbhb writer, HDACs and sirtuins as erasers, and ENL as an H3K9bhb reader. Kbhb has also been linked to CD8⁺ T-cell memory, fasting-responsive chromatin remodeling, tumor metabolic rewiring and non-histone protein regulation. However, shared enzymes, overlapping acylation programs and pleiotropic BHB signaling complicate causal attribution.

Kbhb should not be viewed as uniformly beneficial or pathological. Instead, its effects depend on donor availability, site specificity, reader engagement, tissue context, disease stage and competing acylations. Future work should prioritize site-resolved mass spectrometry, validated chromatin profiling, parallel acylome analysis, functional perturbation and clinically interpretable biomarkers to define which Kbhb events are causal and therapeutically actionable.