Crosstalk between lactylation and other post-translational modifications in health and diseases.

The inherent perception of lactate as the byproduct of glycolysis has been transformed by the discovery of lysine lactylation (Kla). Lactylation modification, a reversible and precise acylation, occurs on both histones and non-histone proteins and directly regulates epigenetics and the diversity of various protein functional activities. Since the discovery of lactylation, it has become evident that lactylation does not act in isolation but often works in conjunction with other post-translational modifications (PTMs) such as acetylation, phosphorylation and ubiquitination. On the one hand, lactylation modification shares the similar enzymes, modified sites and substrates with other acylation modifications, leading to functional crosstalk between them. On the other hand, lactylation or other PTMs could alter the protein conformations, amino acid side chain charges or the occupation of special sites, engaging in cooperative or competitive crosstalk, thereby influencing changes in their modification levels, signal transduction, conformation, re-localization and degradation. However, the underlying molecular mechanisms of the diverse crosstalk between lactylation and other PTMs, as well as their roles in various biological processes, have yet to be fully elucidated. Recent advances in quantitative mass spectrometry, isotope tracing, and integrative multi-omics have enabled more reliable detection and dynamic analysis of lactylation-PTM crosstalk, helping to distinguish causal regulation from metabolic correlation. This review integrates current mechanistic and functional evidence, highlighting the roles of lactylation crosstalk in pathophysiological processes and its implications for health and diseases.