Histone acetyltransferase 1 promotes postinfarction inflammatory response by regulation of monocyte histone succinylation

Early activation and phenotypic transformation of monocytes and macrophages are essential for inflammatory activities and tissue repair following myocardial infarction (MI). However, the involvement of histone succinylation in monocyte phenotypic regulation during MI remains poorly understood. Here we show that succinylation, particularly histone H3K23succ, is significantly upregulated in monocytes from both MI patients and male mouse models, correlating with enhanced inflammatory responses. We further reveal that histone acetyltransferase 1 (Hat1) acts as a succinyltransferase essential for catalytic activity, and is upregulated together with histone succinylation in proinflammatory monocytes. Deficiency in Hat1 expression improves cardiac function, reduces infarct size, and suppresses inflammatory responses in infarcted hearts after MI. Mechanistically, Hat1 modulates chromatin accessibility and recruits H3K23 succinylation to regulate proinflammatory gene expression in monocytes and macrophages post-MI. Our study reveals a critical role for histone succinylation in early MI progression and establishes that Hat1 acts as an epigenetic regulator promoting proinflammatory monocyte transformation, highlighting its therapeutic potential for MI treatment. Myocardial infarction triggers inflammation driven by immune cell reprogramming, but the epigenetic regulators involved remain unclear. Here, the authors show that histone acetyltransferase 1 enhances postinfarction inflammation by promoting histone succinylation in monocytes.