Abstract

Background and Purpose Elevated circulating lactate is a recognized prognostic biomarker in septic cardiomyopathy (SCM), yet the mechanisms by which it exacerbates cardiac pathology are not fully understood. This study aims to investigate the role of histone lactylation as a novel epigenetic mechanism linking metabolic dysregulation to myocardial dysfunction in sepsis. Experimental Approach The effects of lactate on lipopolysaccharide (LPS)-induced inflammation and apoptosis were assessed in cardiomyocytes in vitro. The underlying epigenetic mechanism was investigated using CUT&Tag. The role of MYST histone acetyltransferase 1 (MOF) as a lactyltransferase was determined through siRNA knockdown, co-immunoprecipitation and fluorescence co-localization assays. Furthermore, ailanthone (AIL), a specific hexokinase 2 (HK2) inhibitor identified through virtual screening, was evaluated for its therapeutic potential in a murine model of sepsis. Key Results Lactate enhanced LPS-induced cardiomyocyte inflammation and apoptosis. Mechanistically, lactate upregulated histone H4 lysine 16 lactylation (H4K16la). This modification was enriched at the promoters of the CXCL8 and CCL2 genes to drive their transcriptional activation. We further identified MOF as a novel lactyltransferase directly catalysing H4K16la. In vivo, inhibition of HK2 with AIL attenuated myocardial injury and improved cardiac function in septic mice. Conclusion and Implications Our findings reveal a pathogenic axis wherein lactate-driven H4K16la, mediated by MOF, promotes inflammatory gene expression in SCM. This identifies the lactate-H4K16la pathway as a potential therapeutic target for mitigating septic cardiomyopathy. Graphical