lactylation

Lactylation is a post-translational modification in which a lysine residue on a protein is modified by the addition of a lactyl group. It was first described in histones, where histone lysine lactylation (Kla) linked cellular metabolism to epigenetic regulation by reflecting intracellular lactate levels. The modification provides a potential mechanism by which glycolytic flux can influence chromatin state and gene expression.

Biochemically, Kla is thought to be derived from lactyl-CoA, a metabolic intermediate produced from lactate. Enzymatic transfer of the lactyl group has been demonstrated in vitro for histone acetyltransferases such as p300/CBP, indicating that there can be enzyme-catalyzed lactylation. However, non-enzymatic routes may also contribute under certain metabolic conditions. Kla is considered reversible, and research is ongoing to identify the cellular “erasers” that remove lactyl groups; histone deacetylases and related enzymes have been implicated, but the full complement of Kla demodifying enzymes remains under investigation.

Lactylation is not limited to histones; Kla has been detected on non-histone proteins, suggesting broader roles in cellular regulation. The modification is dynamic and responsive to metabolic states, particularly lactate production during glycolysis. In immune cells, such as macrophages, Kla has been associated with gene expression programs linked to tissue repair and anti-inflammatory states, highlighting a potential link between metabolism, chromatin modification, and cell fate decisions.

Detection methods include mass spectrometry and Kla-specific antibodies. Ongoing research aims to define the scope of Kla across tissues, its interplay with other post-translational modifications, and its implications in development, cancer metabolism, and immune responses.