Protective effect of Cyclo(His‐Pro) on peritoneal fibrosis through regulation of HDAC3 expression

Peritoneal dialysis is a common treatment for end‐stage renal disease, but complications often force its discontinuation. Preventive treatments for peritoneal inflammation and fibrosis are currently lacking. Cyclo(His‐Pro) (CHP), a naturally occurring cyclic dipeptide, has demonstrated protective effects in various fibrotic diseases, yet its potential role in peritoneal fibrosis (PF) remains uncertain. In a mouse model of induced PF, CHP was administered, and quantitative proteomic analysis using liquid chromatography–tandem mass spectrometry was employed to identify PF‐related protein signaling pathways. The results were further validated using human primary cultured mesothelial cells. This analysis revealed the involvement of histone deacetylase 3 (HDAC3) in the PF signaling pathway. CHP administration effectively mitigated PF in both peritoneal tissue and human primary cultured mesothelial cells, concurrently regulating fibrosis‐related markers and HDAC3 expression. Moreover, CHP enhanced the expression of nuclear factor erythroid 2‐related factor 2 (Nrf2) while suppressing forkhead box protein M1 (FOXM1), known to inhibit Nrf2 transcription through its interaction with HDAC3. CHP also displayed an impact on spleen myeloid‐derived suppressor cells, suggesting an immunomodulatory effect. Notably, CHP improved mitochondrial function in peritoneal tissue, resulting in increased mitochondrial membrane potential and adenosine triphosphate production. This study suggests that CHP can significantly prevent PF in peritoneal dialysis patients by modulating HDAC3 expression and associated signaling pathways, reducing fibrosis and inflammation markers, and improving mitochondrial function. This graphical illustrates the protective effects of Cyclo(His‐Pro) (CHP) against peritoneal fibrosis (PF) by regulating HDAC3 expression. In a PF‐induced mouse model, CHP treatment reduced fibrosis, pro‐inflammatory molecules, and myeloid‐derived suppressor cells in the spleen. Proteomic profiling identified HDAC3 as a key player in PF pathophysiology. In vitro validation using human primary cultured peritoneal mesothelial cells (HPMCs) showed that CHP mitigated fibrotic injury and oxidative stress, restoring mitochondrial function and reducing cell necrosis.