Macrophage MCT4 inhibition activates reparative genes and protects from atherosclerosis by histone H3 lysine 18 lactylation. Macrophage MCT4 inhibition activates reparative genes and protects from atherosclerosis by histone H3 lysine 18 lactylation

Macrophage activation is a hallmark of atherosclerosis, accompanied by a switch in core metabolism from oxidative phosphorylation to glycolysis. The crosstalk between metabolic rewiring and epigenetic modifications in macrophages is worthy of further investigation. Here, we found that lactate efflux-associated monocarboxylate transporter 4 (MCT4)-mediated histone lactylation is closely related to atherosclerosis. Histone H3 lysine 18 lactylation dependent on MCT4 deficiency activated the transcription of anti-inflammatory genes and tricarboxylic acid cycle genes, resulting in the initiation of local repair and homeostasis. Strikingly, histone lactylation is characteristically involved in the stage-specific local repair process during M1 to M2 transformation, whereas histone methylation and acetylation are not. Gene manipulation and protein hydrolysis-targeted chimerism (PROTAC) technology were used to confirm that MCT4 deficiency favors ameliorating atherosclerosis. Therefore, our study shows that macrophage MCT4 deficiency, which links metabolic rewiring and epigenetic remodeling, plays a key role in training macrophages to become repair and homeostasis phenotypes. Overall design: ox-LDL-induced THP-1-derived macrophages with or without MCT4 deficiency, three samples for each group.