Targeting MLL1 / WDR5 ‐Mediated Epigenetic Regulation Mitigates Peritoneal Fibrosis by Reducing p16 INK4a

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ABSTRACT Peritoneal fibrosis poses a significant challenge to the long‐term efficacy of peritoneal dialysis (PD), with emerging evidence highlighting the role of cellular senescence in its pathogenesis. p16 INK4a is a cell cycle regulator that has been implicated in cellular senescence. Mixed‐lineage leukemia 1 (MLL1) forms a complex with WD‐40 repeat protein 5 (WDR5) and exhibits histone H3K4 methyltransferase activity. We have previously shown that inhibition of the MLL1/WDR5 complex reduces p16 INK4a expression and attenuates renal senescence after injury in mice. This study aimed to investigate whether inhibiting MLL1/WDR5 attenuates peritoneal senescence, inflammation, and fibrosis in both human samples and in mice with methylglyoxal (MGO)‐induced peritoneal fibrosis (MGO‐injected mice), while also exploring the associated underlying mechanisms. MLL1/WDR5, histone 3 lysine 4 trimethylation (H3K4me3), and p16 INK4a expression were elevated in TGF‐β1‐stimulated human peritoneal mesothelial cells (HPMCs), non‐adherent cells obtained from patients undergoing PD, and the submesothelial compact zones of MGO‐injected mice. Notably, p16 INK4a expression in these cells was positively correlated with the dialysate/plasma creatinine ratio. Treatment with the MLL1/WDR5 protein–protein interaction inhibitors MM‐102 and OICR‐9429 reduced H3K4me3 levels and p16 INK4a expression, suppressing fibrosis in HPMCs as well as peritoneal fibrosis and inflammation in MGO‐injected mice. These inhibitors also improved peritoneal function in MGO‐injected mice. Additionally, we demonstrated that MLL1/WDR5‐induced H3K4me3 directly regulates p16 INK4a gene transcription, and that inhibiting MLL1/WDR5 reduces H3K4me3, thereby suppressing p16 INK4a gene transcription. These findings suggest that targeting MLL1/WDR5 activation alleviates peritoneal senescence, inflammation, and fibrosis, highlighting its potential as a promising therapeutic strategy for peritoneal fibrosis.

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