The role and mechanism of histone lactylation in health and diseases

Abstract

Whether under anaerobic or aerobic conditions, glycolysis results in production of lactate. Increasing evidence suggests that lactate serves as a multifunctional signaling molecule that develops non-metabolic activities in addition to serving as a key metabolite to link glycolysis and oxidative phosphorylation. Histone posttranslational modification patterns (HPTMs) are essential epigenetic processes controlling a variety of biological activities. Proteomics based on mass spectrometry (MS) has been used to progressively reveal new HPTMs. Recent discoveries of histone lactylation modification mediated by lactate and subsequent research demonstrating its involvement in cancer, inflammation, lung fibrosis, and other conditions suggest that it plays a significant role in immune regulation and homeostasis maintenance. This review provides a brief overview of the complicated control of histone lactylation modification in both pathological and physiological conditions.

Dual Roles of Lactate in EGFR-TKI-Resistant Lung Cancer by Targeting GPR81 and MCT1

“…Numerous histone modifications, including acetylation, methylation, and crotonylation, have been documented before the 2019 discovery of histone lactylation. Recent findings by Zhao et al state that lactate contributed to epigenetic regulation of genes by lactylating histone lysine residues and that lactate was found to be a precursor to histone lysine lactylation (Kla), which stimulated gene transcription from chromatin [ 24 , 25 ]. Histone lactylation is first reported to promote homeostasis of macrophages during infection, and more and more studies have focused its role in cancer.…”

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

“…3,172 In recent years, the study of epigenetic modifications has gained significant attention, and histone lactylation has been discovered to play a crucial role in immune regulation, inflammation, cancer, and other diseases. [173][174][175][176] The p300 of HAT family mediates the lactylation modification of H3 and H4, while the deacetylases HDAC1-3 and SIRT1-3 have the de-L-lactylase enzyme activity. 171 These results indicate that histone lactate is also a reversible process.…”

“…found that global H3K18 lactylation distribution marked the active promoter regions of some highly expressed genes, which was positively correlated with gene expression 3,172 . In recent years, the study of epigenetic modifications has gained significant attention, and histone lactylation has been discovered to play a crucial role in immune regulation, inflammation, cancer, and other diseases 173–176 …”

An adult Drosophila glioma model to highlight metabolic dysfunctions and evaluate the role of the serotonin 5‐HT7 receptor as a potential therapeutic target

“…93,94 It may act as a signaling molecule and regulate gene expression by acting at the epigenetic level as a precursor of lactylation of histones. 95,96 Glycogen, a form of glucose storage, was also identified as a discriminant metabolite. In Drosophila, it is synthesized and stored mainly in muscles and the fat body.…”