Lysine l-Lactylation: Bridging Metabolism, Chromatin and Disease

Lysine L-lactylation (K_L-la) is a newly identified metabolite-derived post-translational modification that directly bridges cellular metabolic states to chromatin regulation and protein function. Mounting evidence shows that K_L-la has pivotal roles in transcription regulation and diverse cellular processes and is implicated in multiple pathophysiological conditions. This review comprehensively examines K_L-la across both histone and non-histone substrates in biology and disease. We first illustrate the historical development of K_L-la and distinguish it from its isomers. We then delineate the enzymes regulating K_L-la, examine its crosstalk with other PTMs, and discuss its roles in cell signalling and other biological processes. Particular emphasis is placed on mechanisms through which K_L-la contributes to various human diseases such as cancer, viral infections, neurodegenerative disorders, cardiovascular conditions, metabolic abnormalities and immune dysregulation. Finally, we provide an in-depth analysis of emerging therapeutic strategies targeting K_L-la and highlight future directions for translating mechanistic insights into clinical applications.