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

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.