Asiaticoside alleviates mesothelial cell senescence and peritoneal fibrosis by targeting macrophage-mesothelial communication in single-cell peritoneal landscape

BACKGROUND: Peritoneal fibrosis (PF) is a critical factor limiting long-term peritoneal dialysis (PD). The specific composition of peritoneal cells and intercellular communication remain unelucidated in PF context. Asiaticoside (ASI) possesses anti-fibrotic properties, but its therapeutic effects on PD-related PF and underlying mechanisms stay unclear. PURPOSE: To investigate changes in peritoneal cell components and their interactions during PF progression. To explore the pharmacological effects and potential mechanism of ASI against PF. METHODS: A mouse PF model was induced with high-glucose peritoneal dialysis fluid (PDF). Samples of parietal peritoneum were collected for single-cell RNA sequencing. The intercellular communication network was systematically characterized within the PF microenvironment. Immunohistochemistry, immunofluorescence, western blotting, qRT-PCR, and ELISA were conducted to elucidate the specific anti-fibrotic mechanisms of ASI. RESULTS: The single-cell RNA sequencing atlas of PD-induced PF comprises 57,032 single cells classified into seven distinct cell types. Insulin-like growth factor 1 (IGF1) signaling was dysregulated in PF between macrophages and mesothelial cells and regulated mesothelial cell senescence. The accumulation of senescent mesothelial cells and their senescence-associated secretory phenotype (SASP) promoted inflammaging and thereby exacerbated PF. IGF1 supplementation with M2-Mφ supernatants or exogenous IGF1 alleviated mesothelial cell senescence and decreased fibrotic responses in PF mice. Treatment with ASI alleviated mesothelial cell senescence and prevented PF in vivo. ASI inhibited mesothelial cell senescence by enhancing IGF1 signaling in macrophages-mesothelial communication. CONCLUSION: ASI inhibited mesothelial cell senescence via macrophage/IGF1 axis to alleviate PF in single-cell peritoneal landscape. These findings highlight the potential of ASI as a therapeutic agent against PF.