Lactate suppresses innate immunity in Caenorhabditis elegans by excessive activation of SKN-1 associated with histone H4K16 lactylation

Histone lactylation is a recently identified epigenetic modification that directly couples cellular metabolic state with gene expression. Whether lactate affects host resistance to pathogens via histone lactylation remains unclear. Here, we found that infection with Pseudomonas aeruginosa PA14 significantly increased lactate levels in Caenorhabditis elegans . Exogenous sodium lactate (NAL) also raised lactate levels and reduced worm resistance to the extracellular bacteria P. aeruginosa and Enterococcus faecalis , but had no detectable effect on the intracellular bacteria Salmonella and Listeria monocytogenes . Lowering lactate levels with the lactate dehydrogenase inhibitor Oxamate enhanced worm resistance to infection. Genetic screening showed that the regulatory effects of NAL and Oxamate on immunity were dependent on SKN-1. Similar results were also observed with pyruvate and the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA) treatment. Mechanistic studies showed that, among the histone lactylation sites examined, elevated lactate promoted lactylation most strongly at H4K16 (H4K16la). ChIP‑qPCR results showed increased H4K16la enrichment at the skn-1 promoter upon lactate elevation. This led to increased activity of the transcription factor SKN-1, as evidenced by increased SKN-1 nuclear translocation, upregulation of downstream genes ( skn-1 , gst-4 , gst-7 , gst-10 , gcs-1 ), and enhanced GST-4::GFP fluorescence. However, the addition of NAL caused excessive GST-4::GFP fluorescence, indicating SKN-1 overactivation. This also led to suppression of the antimicrobial peptide IRG-1 and increased bacterial accumulation in the gut. In summary, this study provides evidence that lactate suppresses innate immunity in C. elegans , likely through H4K16 lactylation-mediated overactivation of SKN-1. These findings suggest that lactate may act as a negative regulator of innate immunity in an invertebrate model and provide a basis for future studies on targeting lactate metabolism or histone lactylation in infectious diseases.