Lactylation as a metabolic–epigenetic switch: Mechanisms and roles in cancer, sepsis, trauma, inflammation, and tissue repair

Lactylation, a recently discovered post-translational modification, links cellular metabolism to epigenetic regulation and immune function. Once considered a mere glycolytic byproduct, lactate is now recognized as a signaling metabolite that can shape gene expression and protein activity via histone and non-histone lactylation. This review synthesizes evidence on enzymatic and non-enzymatic mechanisms of lactylation, including lactoyl-CoA-dependent pathways, glyoxalase-mediated routes, and emerging functions of aminoacyl-tRNA synthetases. We highlight lactylation “writers” and “erasers,” stereochemical considerations, and integration with other acyl modifications while explicitly distinguishing well-supported mechanisms from hypothesis-generating findings. Functionally, lactylation influences inflammatory signaling, metabolic reprogramming, and immune cell polarization, providing a conceptual link across sepsis, trauma, autoimmune disease, cancer, and tissue repair. Examples include HMGB1 modification cascades in sepsis, macrophage state transitions in inflammation, fibroblast/angiogenic programs in wound environments, and DNA repair regulation in cancer drug resistance. The context-dependence of lactylation adaptive versus pathological, tumor-promoting versus potentially tumor-restrictive underscores the need for temporal, cell-type, and compartment-specific interpretation. We conclude with methodological constraints, translational feasibility, and key priorities for moving lactylation from a mechanistic bridge to a clinical biomarker and therapeutic axis. • Lactate acts as a signaling metabolite influencing gene expression via lactylation. • Lactate modulates immune responses via lactylation in macrophages and other cells. • Lactate-driven lactylation influences tumor microenvironment and cancer progression. • Targeting lactylation pathways offers new therapeutic strategies in disease treatment.