PFKM‐Driven Lactate Overproduction Promotes Atrial Fibrillation via Triggering Cardiac Fibroblasts Histone Lactylation

Increasing evidence has clarified that atrial fibrillation (AF) is associated with enhanced glycolysis, leading to lactate accumulation. However, whether glycolysis promotes AF remains unknown, as does whether histone lactylation plays a role in its pathogenesis. In the study, spontaneous AF mice are established to monitor AF susceptibility and atrial substrates at different ages (3, 5, 7 months), indicating that enhanced glycolysis acts as a promoter during AF development by inducing atrial fibrosis. The promoting effect of glycolysis on AF and the pivotal enzyme in driving glycolysis are confirmed by treatment with glycolysis inhibitor 2-deoxyglucose (2-DG) and adeno-associated virus-mediated atrial PFKM expression. Furthermore, lactate stimulates primary mouse cardiac fibroblast (CF) activation. Mechanistically, the observations indicated that atrial lactate accumulation promotes global lactylation and H3K18 lactylation in atrial fibroblasts. P300-mediated H3K18 lactylation up-regulates TGF-β1 transcription, leading to activation of CF, and thereby contributing to atrial fibrosis. The results reveal a novel role of the metabolic-epigenetic axis in AF pathogenesis, which raises the possibility of potential therapeutic strategies targeting AF.