Interwoven control of histone lactylation: metabolic enzymes LDHA/ACSS2 couple with epigenetic writer KAT2A

Histone lactylation is critically involved in the regulation of gene expression and the modulation of diverse cellular processes in both normal and tumor cells. A recent study by Zhu et al. [Cell Metab. 37, 361–376] demonstrated that ACSS2 functions as a bona fide lactyl-CoA synthetase, converting lactate into lactyl-CoA. In response to elevated aerobic glycolysis and EGFR activation, ERK-mediated phosphorylation drives the nuclear translocation of ACSS2, promoting the formation of the ACSS2–KAT2A complex. KAT2A utilizes ACSS2-derived lactyl-CoA and acts as a lactyltransferase to promote histone lactylation, gene expression, tumor growth, and immune evasion.