Lactate metabolism in human health and disease

Abstract

The current understanding of lactate extends from its origins as a byproduct of glycolysis to its role in tumor metabolism, as identified by studies on the Warburg effect. The lactate shuttle hypothesis suggests that lactate plays an important role as a bridging signaling molecule that coordinates signaling among different cells, organs and tissues. Lactylation is a posttranslational modification initially reported by Professor Yingming Zhao's research group in 2019. Subsequent studies confirmed that lactylation is a vital component of lactate function and is involved in tumor proliferation, neural excitation, inflammation and other biological processes. An indispensable substance for various physiological cellular functions, lactate plays a regulatory role in different aspects of energy metabolism and signal transduction. Therefore, a comprehensive review and summary of lactate is presented to clarify the role of lactate in disease and to provide a reference and direction for future research. This review offers a systematic overview of lactate homeostasis and its roles in physiological and pathological processes, as well as a comprehensive overview of the effects of lactylation in various diseases, particularly inflammation and cancer.

Fig. 1

Lactate metabolism and lactylation in cells. In the cytoplasm, lactate is transported into cells by MCTs and is produced from glycolysis or glutamine decomposition. The catabolism of lactate in cells occurs through two pathways. In one pathway, lactate is oxidized to pyruvate, which enters mitochondria and is metabolized through the tricarboxylic acid cycle. In the other pathway, lactate is converted to glucose through gluconeogenesis. Lactate can be converted into lactyl-CoA and is involved in the lactylation of histones and nonhistone proteins. LDH lactate dehydrogenase; PDH pyruvate dehydrogenase; GLUD glutamate dehydrogenase; HDACs Histone Deacetylases. (Figure was created with Biorender.com.)

Fig. 2

Lactate is involved in the regulation of cellular physiological and pathological processes. In addition to the intracellular production of lactate, lactate can enter target cells through intercellular shuttling involving nonchannel pathways or MCT1. As a signaling molecule or metabolic substrate, lactate is involved in glucose metabolism, fatty acid synthesis, redox homeostasis, and the PTM of proteins. Meanwhile, as a GPR81 ligand, lactate stimulates the GPR81 signaling pathway. Lactate has been shown to regulate muscle contraction, wound healing, memory formation, and tumor development. MCT monocarboxylate transporter; OXPHOS oxidative phosphorylation; GLUT glucose transporter. (Figure was partly created with SMART – Servier Medical ART)

Fig. 3

Mechanism by which lactylation promotes tumorigenesis. Lactylation leads to tumor immunosuppression by maintaining TAM homeostasis. Lactylation directly promotes the expression of the oncogene YTHDF2 in tumor cells. Lactylation maintains the metabolic homeostasis of tumor cells. Lactylation may lead to tumor immunosuppression and immune escape by inhibiting the function of various immune cells in the TME. HK-1 hexokinase-1; G6PD glucose-6-phosphate dehydrogenase; PKM pyruvate kinase; SDH succinate dehydrogenase; IDH isocitrate dehydrogenase; TCA cycle tricarboxylic acid cycle

Fig. 4

Lactate contributes to various diseases. Lactate is involved in the regulation of cardiovascular system, respiratory system, digestive system, urinary system, and other diseases. Lactate plays an important role in clinical diagnosis and prognosis of diseases. (Figure was created with Biorender.com)