Metabolic-Epigenetic Mechanism of Peritoneal Fibrosis Targeted by Mesenchymal Stem Cell-Derived Extracellular Vesicles

Background: Peritoneal fibrosis is a fibroproliferative disorder defined by persistent inflammation and aberrant tissue repair, with limited therapeutic options currently available. This study aimed to evaluate the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in attenuating peritoneal fibrosis and to elucidate their underlying mechanisms. Methods: A chlorhexidine gluconate (CG)-induced peritoneal fibrosis mouse model was treated with human bone marrow MSC-EVs. Single-cell RNA sequencing (scRNA-seq) was performed on peritoneal tissues to analyze cellular interactions. Metabolic reprogramming in injured mesothelial cells was assessed via glycolysis and lactate production assays.Mechanistic insights into epigenetic modulation were explored through histone H3K18 lactylation analysis and CCL2 transcriptional regulation studies. Results: MSC-EVs significantly alleviated CG-induced peritoneal fibrosis by reducing inflammation, collagen deposition, and angiogenesis. scRNA-seq revealed that MSC-EVs disrupted mesothelial cell-macrophage crosstalk by suppressing the Ccl2-Ccr2 ligand-receptor axis. Mechanistically, MSC-EVs attenuated hyperglycolysis and lactate production in injured mesothelial cells, which inhibited CCL2 transcription via H3K18 lactylation-dependent epigenetic modulation. Pharmacological inhibition of lactate production mirrored the anti-fibrotic effects of MSC-EVs, further confirming the critical role of metabolic reprogramming. Conclusion: These findings highlight lactate-induced histone lactylation as a key driver of peritoneal fibrosis and position MSC-EVs as a promising cell-free therapeutic strategy for targeting metabolic-epigenetic inflammation in serosal injury.