Histone lactylation encodes innate immune memory in atherosclerosis: a hypothesis of epigenetic bookmarking for residual inflammatory risk

Abstract

Histone lactylation, particularly H3K18 lactylation (H3K18la), has emerged as a lactate-derived epigenetic modification that links metabolic reprogramming to sustained chromatin states. Here, we advance a hypothesis that the lactate-p300-H3K18la axis functions as an epigenetic memory code, converting transient glycolytic signals into persistent transcriptional responsiveness in innate immune cells—a mechanism we term “context-dependent lactylation memory.” We integrate evidence from three converging domains: the persistence of lactylation at trained immune loci, the requirement of H3K18la for trained immunity demonstrated in recent BCG vaccination studies, and the hypoxic, glycolytic microenvironment of the atherosclerotic plaque. We propose that cardiovascular risk factors stabilize HIF-1α, which drives glycolytic reprogramming and sustained lactate production. Lactate-derived lactyl-CoA then serves as a substrate for p300/CBP-mediated H3K18la deposition at immune gene regulatory elements, creating a poised chromatin state that sustains innate immune hyperresponsiveness. This cascade provides a mechanistic explanation for residual inflammatory risk, the observation that elevated cardiovascular events persist despite optimal lipid-lowering therapy. The framework is constrained by the context-dependent duality of lactylation, whereby cell type, lysine site, and metabolic flux direction jointly determine whether the modification drives pro-inflammatory or reparative outcomes. We delineate testable predictions that define a roadmap for empirical validation or refutation of the lactate–lactylation memory hypothesis in human CHD.