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

作者：Yunjia Zhang, Hong Jiang, Mengdie Dong, Jiao Min, He Xian, Yongkang Tan, Fuhao Liu, Minghong Chen, Xiang Chen, Quanwen Yin, Longbin Zheng, Yongfeng Shao, Xuesong Li, Hongshan Chen · 发表于：Cell Reports · 年份：2024 · DOI：10.1016/j.celrep.2024.114180 · 被引用次数：106 · 研究领域：Immune cells in cancer、Epigenetics and DNA Methylation、MicroRNA in disease regulation

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 histone modifications in macrophages is worthy of further investigation. Here, we find 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 technology are used to confirm that MCT4 deficiency favors ameliorating atherosclerosis. Therefore, our study shows that macrophage MCT4 deficiency, which links metabolic rewiring and histone modifications, plays a key role in training macrophages to become repair and homeostasis phenotypes.