Lysine l ‐Lactylation: Bridging Metabolism, Chromatin and Disease

ABSTRACT 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.