Interplay between N6-methyladenosine RNA methylation and protein lactylation: a novel crosstalk linking metabolism and epigenetic regulation in human diseases

Abstract

N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification in eukaryotic mRNA and precisely regulates gene expression by regulating the RNA life cycle. Lactate, a central glycolytic metabolite, can transduce cellular metabolic states into epigenetic signals through protein lactylation, an emerging post-translational modification. Because both modifications are highly responsive to cellular metabolic status, they have emerged as important regulators of the metabolic-epigenetic interface. Increasing evidence supports a bidirectional regulatory crosstalk between m6A modification and protein lactylation. Lactate accumulation can modulate the expression and activity of m6A-related regulatory enzymes through histone and non-histone lactylation; conversely, m6A modification can reshape glycolysis and lactate metabolism, thereby altering lactate availability and protein lactylation. This reciprocal regulation has been implicated in a broad spectrum of diseases, including cancer, metabolic disorders, cardiovascular diseases, and immune-inflammatory conditions. In this review, the molecular mechanisms of m6A modification and protein lactylation are systematically summarized, with particular emphasis on their modes of interaction and pathological relevance. Current limitations and future perspectives are also discussed, providing a conceptual framework for elucidating disease mechanisms and developing therapeutic strategies targeting this regulatory network.