Lactate-induced lactylation: from basic research to clinical perspectives

Abstract

Lactate was initially considered a metabolic waste product of glycolysis under hypoxic conditions until the emergence of the lactate shuttle hypothesis. The lactate shuttle hypothesis describes the role of lactate in the delivery of oxidative and gluconeogenic substrates as well as in cell signaling. Lactate is a key molecule that links cellular metabolism to the regulation of cellular activity. Lactate-induced lactylation was first identified and reported in Nature in 2019 by Zhang et al. Subsequently, many studies on lactylation have been reported. Widely distributed lactylation is involved in a myriad of pathological processes and participates in the development and progression of numerous diseases, offering promising potential for future disease treatments. We comprehensively reviewed and organized the existing literature, detailed the metabolic processes of lactate and lactylation, and summarized the existing research methods on lactylation, aiming to provide direction and convenience for future research in this field. Additionally, we summarized the role of lactylation in various pathophysiological processes and elucidated the relationship between lactate modification and various diseases, as well as the targets and drugs that regulate lactylation, which may enable future clinical interventions.

Keywords: complex diseases; lactate; lactylation; metabolic processes; pathophysiological processes.

FIGURE 1

Production and transport of lactate in cells. Glucose is converted into pyruvate through glycolysis. Pyruvate then enters the mitochondria, where it is converted to acetyl-CoA by pyruvate dehydrogenase (PDH), which then enters TCA cycle under aerobic conditions for efficient production. However, under hypoxic conditions, pyruvate is converted to lactate in the cytoplasm by lactate dehydrogenase (LDH). Lactate, inside and outside of cells, can be transported through MCT. In addition, lactate can activate GPR81, initiating signaling molecular effects. Lactate converted from glucose in muscles can be transported to the liver, where it is converted into glucose via gluconeogenesis. This glucose is then released into the bloodstream and reabsorbed by muscles. This process forms a cycle called the lactate cycle (Cori cycle).

FIGURE 2

Regulatory mechanisms of lactylation. Lactate produced by glycolysis or entering from outside the cell binds to CoA to form lactoyl-CoA. This lactoyl-CoA acts as a direct substrate for lactylation, where it binds to and dissociates from lysine residues in proteins, a process facilitated by “writer” and “eraser”. The “reader” protein recognizes lactylation changes, influencing downstream signaling pathways and triggering biological events. Histone lactylation regulates gene transcription by modulating the interaction between histones and DNA. In contrast, non-histone lactylation mainly modifies proteins through the addition of the lactoyl group, regulating protein activity and function. Both forms of lactylation are widely involved in various biological processes.