Chen Jingquan, Liu Zongrong, Yue Zhujun, Tan Qiang, Yin Hongshun, Wang Haifei, Chen Zhilong, Zhu Yanbing, Zheng Jianghua
Department of Vascular Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China.
Department of Vascular Surgery, North Sichuan Medical College, Nanchong 637000, China.
Biochim Biophys Acta Gen Subj. 2025 Aug;1869(9):130838. doi: 10.1016/j.bbagen.2025.130838. Epub 2025 Jun 28.
Macrophages, as the primary immune cell population in atherosclerosis (AS), exhibit complex pathogenic mechanisms that are not fully elucidated. This study aims to explore the interplay between histone lactylation and methyltransferase-like protein 3 (METTL3)-mediated m6A modification and their potential mechanisms in AS. We demonstrate that METTL3 is highly expressed in macrophages in both in vivo and in vitro models of atherosclerosis, and myeloid cell-specific deletion of METTL3 attenuates the progression of atherosclerosis. Furthermore, the accumulation of lactate levels in macrophages promotes METTL3 expression through EP300-mediated histone H3 lysine 18 lactylation (H3K18la) binding to the METTL3 promoter site. We found that METTL3-mediated m6A modifications are enriched in solute carrier family 7 member 11 (SLC7A11) and accelerate its mRNA degradation in a YTH domain family member 2 (YTHDF2)-dependent manner, thereby promoting ferroptosis in macrophages. Additionally, lactate stimulation downregulates SLC7A11 through the METTL3/YTHDF2 pathway, further promoting ferroptosis. Overall, during AS, lipid peroxidation induces an increase in lactate levels within macrophages, which enhances METTL3 expression through EP300-mediated H3K18la. This further accelerates the degradation of SLC7A11 mRNA via the YTHDF2-dependent m6A modification pathway, inducing ferroptosis in macrophages. This discovery provides new insights into the mechanisms of macrophage function in AS and offers a theoretical basis for the development of therapies for AS.
巨噬细胞作为动脉粥样硬化（AS）中的主要免疫细胞群体，其复杂的致病机制尚未完全阐明。本研究旨在探讨组蛋白乳酸化与甲基转移酶样蛋白3（METTL3）介导的m6A修饰之间的相互作用及其在AS中的潜在机制。我们证明，在动脉粥样硬化的体内和体外模型中，METTL3在巨噬细胞中高表达，并且髓系细胞特异性缺失METTL3可减轻动脉粥样硬化的进展。此外，巨噬细胞中乳酸水平的积累通过EP300介导的组蛋白H3赖氨酸18乳酸化（H3K18la）与METTL3启动子位点结合来促进METTL3表达。我们发现，METTL3介导的m6A修饰在溶质载体家族7成员11（SLC7A11）中富集，并以YTH结构域家族成员2（YTHDF2）依赖的方式加速其mRNA降解，从而促进巨噬细胞中的铁死亡。此外，乳酸刺激通过METTL3/YTHDF2途径下调SLC7A11，进一步促进铁死亡。总体而言，在AS过程中，脂质过氧化导致巨噬细胞内乳酸水平升高，通过EP300介导的H3K18la增强METTL3表达。这进一步通过YTHDF2依赖的m6A修饰途径加速SLC7A11 mRNA的降解，诱导巨噬细胞中的铁死亡。这一发现为AS中巨噬细胞功能的机制提供了新的见解，并为AS治疗的开发提供了理论基础。
