Lactate-Induced H3K18 Lactylation Drives CX3CL1-Mediated Immune Cell Recruitment in Sepsis-Associated ARDS

Sepsis is characterized by lactate accumulation and immune dysfunction, but the molecular mechanisms linking lactate to chemokine expression remain unclear. Here, we investigated whether lactate regulates chemokine transcription through histone lactylation. Human peripheral blood mononuclear cells (PBMCs) were treated with lactate (LAC group) or PBS control (CON group), followed by RNA sequencing (RNA-seq) to identify differentially expressed genes. Chromatin immunoprecipitation sequencing (ChIP-seq) using H3K18la-specific antibody was performed to detect lactylation-enriched gene promoters. Integration of RNA-seq and ChIP-seq data identified CX3CL1 as a lactylation-regulated chemokine. Functional assays demonstrated that lactate-induced H3K18la promotes CX3CL1 expression, enhances PBMC migration, and facilitates T cell recruitment in vitro. In a cecal ligation and puncture (CLP)-induced sepsis-associated acute respiratory distress syndrome (ARDS) mouse model, elevated lactate increased pulmonary CX3CL1 expression and immune cell infiltration, whereas inhibition of lactate production reduced these effects. These data reveal a lactate–H3K18la–CX3CL1 axis that mediates immune cell recruitment and exacerbates sepsis-related lung injury.