Lactate metabolism and epigenetic reprogramming in cancer: beyond energy metabolism to chromatin dynamics

Metabolic reprogramming and epigenetic remodeling represent interconnected hallmarks of cancer progression. Lactate, traditionally regarded as a terminal product of aerobic glycolysis, is now recognized as a metabolically active molecule that participates in signaling regulation and epigenetic modulation within tumor cells and the tumor microenvironment. Accumulating evidence indicates that lactate metabolism influences multiple layers of epigenetic regulation, including DNA methylation, histone modifications, RNA epitranscriptomic regulation, and chromatin organization. Mechanistically, lactate metabolism may affect DNA methylation by altering the availability of metabolic cofactors, including S-adenosylmethionine (SAM), α-ketoglutarate (α-KG), and 2-hydroxyglutarate (2-HG), thereby modulating the activity of DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes. In addition, lactate-derived lysine lactylation(Kla), mediated primarily by p300-dependent mechanisms, has emerged as a novel histone modification linking cellular metabolism with transcriptional regulation. Kla has also been reported on non-histone proteins, including some epigenetic regulators, suggesting additional links between lactate metabolism and epigenetic control. Furthermore, lactate-associated changes in histone Kla may affect the expression or activity of RNA-modifying enzymes, including METTL3, FTO, ALKBH5, and NSUN2, thereby linking lactate metabolism to RNA modifications such as N6-methyladenosine (m⁶A) and 5-methylcytosine (m⁵C). Lactate-associated metabolic changes may also influence chromatin remodeling and accessibility. Based on these mechanisms, therapeutic strategies targeting the lactate metabolism-epigenetic regulatory axis—such as p300 inhibitors, lactate dehydrogenase (LDH) inhibitors, and RNA-modifying enzyme inhibitors—hold considerable potential for precision cancer therapy. This review provides a critical evaluation of how lactate-driven epigenetic alterations dynamically modulate gene expression, chromatin accessibility, and 3D genomic architecture. We further discuss the context-dependent effects of lactate-associated epigenetic remodeling on tumor biology and the challenges of therapeutic translation. By dissecting current mechanistic controversies, physiological limits, and clinical translational hurdles, we outline therapeutic strategies targeting lactate-driven chromatin dynamics to overcome refractory malignancies.