The crosstalk between RNA m6A modification and protein lactylation: emerging insights into tumor progression.

N6-methyladenosine (m6A) is one of the most important RNA modifications and is widely distributed across mRNAs and non-coding RNAs. Its deposition, removal, and recognition are dynamically regulated by a set of proteins, including methyltransferases (writers), demethylases (erasers), and binding proteins (readers). Through these regulators, m6A modifications influence key aspects of RNA metabolism, including stability, splicing, nuclear export, and translation efficiency, dynamically regulating cell fate. Protein lactylation is a reversible post-translational modification occurring on lysine residues of both histones and non-histones, with lactate or lactyl-CoA serving as the substrate. Lactylation modulates protein properties, including structure, function, and activity, thereby influencing gene expression. RNA m6A modifications and protein lactylation significantly regulate the biological behaviors of tumors, including proliferation, invasion, metastasis, metabolic reprogramming, immune evasion and treatment resistance. In recent years, their crosstalk has garnered increasing attention. On one hand, m6A regulatory proteins can be regulated by lactylation, either directly or via histone lactylation-mediated epigenetic regulation. On the other hand, m6A modifications may promote protein lactylation by regulating glycolysis and lactate production. This bidirectional interaction forms a regulatory loop that influences tumor progression. This review summarizes the emerging role of the crosstalk between RNA m6A modification and protein lactylation in tumor progression.