Mesenchymal Stem Cell‐Derived Extracellular Vesicles Modulate the Course of Peritoneal Inflammation Through Metabolic and Epigenetic Regulation

Abstract Peritoneal dialysis (PD), as a renal replacement therapy, relies heavily on the structural and functional integrity of the peritoneum. In some patients, however, the peritoneum may undergo adverse remodeling and fibrotic thickening, resulting in treatment failure. Here, a previously unrecognized metabolic‐epigenetic mechanism contributing to peritoneal fibrogenesis is uncovered, wherein lactate accumulation in injured peritoneal mesothelial cells promotes histone H3K18 lactylation and transcriptional activation of macrophage‐recruiting chemokine CCL2. In a mouse model of peritoneal fibrosis induced by chlorhexidine gluconate (CG) or PD fluid, the administration of extracellular vesicles derived from human bone marrow mesenchymal stem cells (MSC‐EVs) significantly ameliorates histological and functional changes in the peritoneum. Single‐cell RNA sequencing reveals that MSC‐EVs attenuate mesothelial‐macrophage crosstalk by suppressing CCL2 signaling. Mechanistically, MSC‐EVs reprogram glycolytic metabolism in mesothelial cells, reduce lactate production, and inhibit H3K18 lactylation‐dependent transcriptional activation of CCL2. Pharmacologic blockade of lactate production recapitulates the protective effects of MSC‐EVs. These findings suggest that lactate‐induced histone lactylation is a key driver of peritoneal fibrosis, positioning MSC‐EVs as a promising cell‐free therapeutic strategy for targeting metabolic‐epigenetic inflammation in serosal injury.