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

## TL;DR

This study shows that extracellular vesicles from stem cells can reduce peritoneal inflammation and fibrosis by targeting metabolic and epigenetic changes.

## Contribution

The study identifies a novel lactate-driven epigenetic mechanism in peritoneal fibrosis and proposes MSC-EVs as a cell-free therapeutic strategy.

## Key findings

- MSC-EVs reduce peritoneal fibrosis by inhibiting lactate-induced H3K18 lactylation and CCL2 activation.
- Pharmacologic lactate blockade mimics the protective effects of MSC-EVs in peritoneal injury models.
- MSC-EVs disrupt mesothelial-macrophage communication by suppressing CCL2 signaling.

## 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.

MSC‐EVs alleviate peritoneal inflammation and fibrogenesis by disrupting the H3K18la‐CCL2 axis and crosstalk between mesothelial cells and Ly6c2⁺ macrophages. Model cartoons are constructed using the Biorender website (https://www.biorender.com/), and a usage license is obtained.