Lactylation of histone H3K18 promotes autophagic gene expression to mitigate immunosuppression in sepsis.

Abstract

Sepsis-induced immunosuppression is associated with both autophagy impairment and glycolytic dysfunction. However, it is unclear how metabolic dysfunction drives epigenetic reprogramming, thereby reducing autophagy in sepsis. Here, we demonstrate that glycolytic dysfunction and consequent lactate deficiency epigenetically silence autophagy by reducing histone H3 lysine 18 lactylation (H3K18la). Using LPS-tolerant macrophages and CLP-induced immunosuppressive murine models, we observed that reduced lactate levels and global lactylation correlated with impaired autophagic flux and diminished bacterial clearance, with H3K18la emerging as the most consistently downregulated histone lactylation mark. Mechanistically, CUT&Tag-seq revealed ATG5 and ATG16L1 as direct transcriptional targets of H3K18la. Moreover, lactate supplementation restored H3K18la deposition, upregulated ATG5/ATG16L1 expression, and rescued autophagy and bactericidal function. Then a lactylation-deficient H3K18R mutation abolished lactate-mediated rescue, while overexpression of ATG5/ATG16L1 restored autophagy even under H3K18la-deficient conditions. Overall, these findings implicate H3K18la as a metabolic-epigenetic checkpoint linking glycolysis to autophagy gene expression, providing a mechanistic framework for understanding how metabolic dysfunction may contribute to immunosuppression in sepsis.