Lactylation, a Novel Metabolic Reprogramming Code: Current Status and Prospects

Abstract

Lactate is an end product of glycolysis. As a critical energy source for mitochondrial respiration, lactate also acts as a precursor of gluconeogenesis and a signaling molecule. We briefly summarize emerging concepts regarding lactate metabolism, such as the lactate shuttle, lactate homeostasis, and lactate-microenvironment interaction. Accumulating evidence indicates that lactate-mediated reprogramming of immune cells and enhancement of cellular plasticity contribute to establishing disease-specific immunity status. However, the mechanisms by which changes in lactate states influence the establishment of diverse functional adaptive states are largely uncharacterized. Posttranslational histone modifications create a code that functions as a key sensor of metabolism and are responsible for transducing metabolic changes into stable gene expression patterns. In this review, we describe the recent advances in a novel lactate-induced histone modification, histone lysine lactylation. These observations support the idea that epigenetic reprogramming-linked lactate input is related to disease state outputs, such as cancer progression and drug resistance.

Keywords: epigenetic; lactate; lactylation; macrophage; posttranslational modification.

Figure 1

Lactate metabolism is implicated in the tumor microenvironment. (A) The main biochemical players in lactate generation: the glycolytic pathway and OXPHOS. (B) Role of lactate in the TME, including tumor, stromal, immune cells, blood vessels and cellular metabolites such as lactate. As a consequence of the Warburg effect and the lactate shuttle, lactate accumulation induces acidosis, angiogenesis, immunosuppression, and tumor cell proliferation and survival.

Figure 2

Lactate-induced epigenetic alterations that shape the cellular phenotype. (A) Stimuli that activate glycolysis and induce metabolic rewiring can induce epigenetic remodeling through histone modifications, thereby resulting in cellular fate decisions. The enzymes that catalyze the production of the intermediate molecule lactyl-CoA, from which histone lactylation is derived, and those that deposit (writers), remove (erasers) or recognize and interpret (readers) histone lactylation remain to be elucidated. (B) An increase in lysine lactylation is delayed after macrophage polarization or somatic cell reprogramming. This delay correlates with changes in the expression of homeostatic genes involved in maintaining biological homeostasis but not with changes in inflammatory gene expression. Lactylation generates a lactate clock to restore normal tissue function after stimulation.