Abstract

Intestinal barrier dysfunction and NLRP3 inflammasome-mediated pyroptosis are critical pathological drivers of dextran sulfate sodium (DSS)-induced colitis, with limited targeted therapies available. Herein, the therapeutic potential of geniposide and its core mechanism were explored. Geniposide was found to ameliorate colitis in a dose-dependent manner, with 50/100 mg/kg doses showing the most efficacy. This was reflected by restored body weight, reduced DAI score and alleviated histological damage in colonic tissues. Notably, the NF-κB-NLRP3-pyroptosis axis was uniquely suppressed by geniposide. Specifically, NF-κB activation was inhibited. The mRNA expression of NLRP3 and CASPASE-1 were downregulated, and the assembly process of the inflammasome was blocked. GSDMD-mediated pyroptosis in intestinal epithelial cells was also abrogated both in vivo and in vitro . Concomitantly, intestinal barrier integrity was synergistically restored. This restoration was achieved via upregulation of tight junction mRNA expression ( OCCLUDIN , ZO-1 , CLAUDIN-1 ) and enhanced MUC-2 secretion. Minor reduction in pro-inflammatory cytokines and inhibition of myeloperoxidase activity were observed as secondary effects. Collectively, geniposide exerts therapeutic effects by targeting the NF-κB-NLRP3-GSDMD pathway. It synergistically inhibits pyroptosis and repairs intestinal barrier, with its innovative value for colitis treatment highlighted.