Inhibition of Caspase‐1 Suppresses GSDMD‐mediated Peritoneal Mesothelial Cell Pyroptosis and Inflammation in Peritoneal Fibrosis

Abstract Pyroptosis, belonging to programmed cell death, is shown to be mediated by gasdermin D (GSDMD) and gains more and more attention in innate immunity and multiple diseases. However, the role of GSDMD‐mediated pyroptosis in peritoneal fibrosis (PF) remains unclear. This study observed NLRP3 inflammasome activation and pyroptosis in the peritoneum of long‐term peritoneal dialysis (PD) patients with PF. Moreover, it is found that high glucose (HG) can induce the activation of NLRP3 inflammasome by regulating TLR4/NF‐κB and JNK/p38 MAPK signaling in human peritoneal mesothelial cells (HPMCs), leading to subsequent Caspase‐1 activation. The cleaved Caspase‐1 promoted pyroptosis‐related transmembrane pore formation through activating GSDMD‐N, and stimulated the HPMCs to secrete inflammatory factors including IL‐1β and IL‐18. GSDMD global deletion or pharmacologic pretreatment with Caspase‐1 specific inhibitor VX‐765 effectively inhibited the pyroptosis and inflammation, thereby ameliorating PF. Additionally, treatment with VX‐765 and transfected with Caspase‐1 siRNA or GSDMD siRNA also inhibited the transmembrane pore formation and inflammatory factors secretion in HG‐induced HPMCs. Consistent with these results, delayed treatment with VX‐765 also alleviated PF, indicating the therapeutic effect of VX‐765. Taken together, the results demonstrate that pyroptosis may be a novel therapeutic target for peritoneal fibrosis.