H3K18 lactylation promotes allergic airway inflammation in asthma via a CSF1/CSF1R/MAPK autocrine axis

Metabolic reprogramming of airway epithelial cells is a hallmark of asthma, yet the mechanisms by which altered metabolism drives inflammation remain largely unknown. Histone lactylation, a recently identified metabolism-derived epigenetic modification, may provide a mechanistic link.

Clinical specimens and single-cell RNA sequencing (scRNA-seq) were analyzed to map the metabolic landscape of asthma. Histone lactylation in airway epithelial cells was assessed by western blotting and immunofluorescence. Functional roles of histone lactylation were evaluated via modulation of glycolysis, lactate availability, or P300 expression. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) were performed to identify transcriptional targets of H3K18 lactylation (H3K18la).

Glycolysis and histone lactylation, particularly H3K18la, were significantly elevated in the airway epithelial cells of asthma. Inhibition of glycolysis or P300 knockdown attenuated the inflammatory response by suppressing histone lactylation; whereas lactate supplementation exacerbated inflammation by promoting histone lactylation. H3K18la accumulated at the CSF1R promoter, directly enhancing its transcription and establishing a CSF1/CSF1R/MAPK autocrine positive feedback axis that positions airway epithelial cells as an upstream driver and inflammatory amplifier in allergic airway inflammation.

This study defines a glycolysis-histone lactylation-CSF1R signaling axis that links epithelial metabolic reprogramming to sustained inflammatory gene activation in asthma, highlighting histone lactylation as a potential therapeutic target for allergic airway inflammation.