The roles of lactate and the interplay with m6A modification in diseases

Abstract

Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation to regulate gene transcription, influencing the activity of T lymphocytes, NK cells, and macrophages in immune suppression, activating G protein-coupled receptor 81 for signal transduction, and serving as an energy substrate. The m⁶A modification represents the most prevalent post-transcriptional epigenetic alteration. It is regulated by m⁶A-related regulatory enzymes (including methyltransferases, demethylases, and recognition proteins) that control the transcription, splicing, stability, and translation of downstream target RNAs. Lactate-mediated lactylation at histone H3K18 can modulate downstream target m⁶A modifications by enhancing the transcriptional expression levels of m⁶A-related regulatory enzymes. These enzymes play a crucial role in the progression of diseases such as cancer, fibrosis (in both liver and lung), myocardial ischemia, cerebral hemorrhage, and sepsis. Furthermore, m⁶A-related regulatory enzymes are also subject to lactylation by lactate. In turn, these regulatory enzymes can influence key glycolytic pathway enzymes or modify lactate transporter MCT4 via m⁶A alterations to impact lactate levels and subsequently affect lactylation processes.

Keywords: Glycolysis; Lactate; Lactylation; M6A modification.

Fig. 1

Extracellular glucose enters the cell through the action of GLUT1, which is regulated by AMPK. Subsequently, a series of enzymes including HK2, PFKM, ALDO, PGM1, and PKM2 work together to produce pyruvate. Pyruvate is then converted into lactate by LDH. Furthermore, pyruvate participates in the TCA cycle with the assistance of PDH and PDK1/2. MCT1 facilitates the transport of extracellular lactate into the cell while MCT4 is responsible for exporting intracellular lactate from the cell. Lactate plays a role in promoting lactyl-CoA production and contributes to histone or non-histone lactylation under the writers, erasers or readers. Additionally, lactate activates the GPR81 receptor, can be involved in immune regulation and serves as a substrate for energy metabolism

Fig. 2

Lactate regulates m⁶A-RRE (METTL3, YTHDF2, YTFDF1 and FTO) by lactylating histone H3K18, thereby mediating the modification of downstream target m⁶A to affect the expression level of target gene. Additionally, it mediates m⁶A modification of target genes through non-histone METTL3 (K281, K345) and METTL16 (K229) lactylation. Furthermore, lactate also regulates YTHDF2-mediated FOXO3 mRNA-m⁶A through an unknown mechanism. In turn, these regulatory enzymes can influence key glycolytic pathway enzymes or modify MCT4 lactate transporter via m⁶A alterations to impact lactate level