Biochemistry and regulation of histone lysine L-lactylation

Histone L-lactylation is a newly identified, metabolism-linked short-chain Lys acylation. Mounting evidence indicates that Lys L-lactylation has key roles in transcription regulation and many other cellular processes and is associated with diverse pathophysiological changes. In this Review, we discuss the unique features of histone L-lactylation, emphasizing the differences between L-lactylation and its isomers, such as D-lactylation. We discuss the regulation of L-lactylation by writers and erasers, its readers and its cofactor L-lactyl-CoA. We highlight the dynamic regulation of nuclear L-lactyl-CoA and L-lactyl-CoA synthetases, which are crucial determinants of the specificity of histone Lys L-lactylation. We also discuss an emerging L-lactyl-CoA-independent L-lactylation pathway. By integrating these findings, we aim to deepen our understanding of the biochemistry and regulation of histone L-lactylation and its broad biological significance.