Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications

Protein lysine lactylation (Kla) is a newly identified post-translational modification (PTM), in which lactyl groups are transferred to specific lysine residues in proteins. As a crucial intermediary between cellular metabolism and epigenetic regulation, Kla immensely increases the functional diversity of the proteome. This intriguing modification extends beyond histones to non-histone proteins, signaling molecules, enzymes, and substrates. In addition to enzymatic L-lactylation utilizing lactate as a lactyl donor and involving enzymes including writers (lactyltransferases), readers (lactylation-binding enzymes), erasers (delactylases), and lactyl-coenzyme A (lactyl-CoA) synthases, non-enzymatic D-lactylation derived from the glyoxalase II substrate S-D-lactoylglutathione (SLG) has also been identified. Emerging evidence underscores the molecular significance of Kla, including gene transcriptional activation, protein stability, enzyme activity, protein‒protein interactions, protein subcellular translocation, crosstalk with other PTMs, RNA modification, epigenetic instability, and phase separation, in orchestrating diverse biological processes. Functionally, Kla plays a fundamental role in physiology, such as somatic cell reprogramming, as well as embryonic, neural, and cochlear development, by regulating gene expression, cell cycle progression, and signal transduction. Conversely, dysregulated Kla renders extensive impacts on the pathogenesis of various diseases, including cancer, neuropsychiatric disorders, cardiovascular and ophthalmic diseases, and immunoinflammatory and metabolic dysregulation, through modulating immune homeostasis, metabolic adaptation, and epigenetic remodeling. This review systematically elucidates the molecular regulatory mechanisms and biological significance of Kla while comprehensively summarizing its involvement in both physiology and pathology. Furthermore, we emphasize the translational potential of Kla as a diagnostic or prognostic biomarker and therapeutic target, offering novel insights for future research and development of innovative therapeutic strategies.