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

TL;DR

Lactate, once seen as a waste product, is now understood to act as a signaling molecule that modifies proteins and influences gene activity, impacting cancer, inflammation, and tissue healing.

Contribution

This paper reviews how lactylation connects metabolism to epigenetics and immune function, offering new insights into disease mechanisms and potential therapies.

Findings

Lactylation modifies histones and non-histone proteins, linking metabolism to gene regulation.

Lactylation affects immune cell function, tumor progression, and tissue repair processes.

Targeting lactylation pathways could lead to new treatments for cancer and inflammatory diseases.

Abstract

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.

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.

Figures