6-Bromoindole-3-acetonitrile Attenuates DSS-Induced Colitis by Inhibiting Epithelial Cell Pyroptosis

Ulcerative colitis is a chronic inflammatory bowel disease that requires new treatment approaches beyond traditional anti-inflammatory drugs. In this study, we analyzed publicly available single-cell RNA sequencing data from a DSS-induced colitis mouse model and identified pyroptosis as a key biological process linked to epithelial damage. Based on this, we screened marine-derived brominated indoles for potential pyroptosis inhibitors and identified 6-bromoindole-3-acetonitrile as a promising candidate. Our results show that this compound significantly alleviates DSS-induced colitis in mice, with notable body weight recovery and a drop in Disease Activity Index (DAI) scores from about 8.5 to below 4 (p < 0.05). At the molecular level, it lowers the mRNA levels of Nlrp3, Caspase-1, and other pyroptosis-related genes, indicating suppression of the pyroptotic pathway. Moreover, treatment helps restore the intestinal barrier by supporting goblet cell regeneration and strengthening tight junctions. Molecular docking suggests that 6-bromoindole-3-acetonitrile binds stably to the active site of myeloperoxidase (MPO), with a binding energy of −18.1 kcal/mol, offering a possible structural basis for its anti-inflammatory effects. Together, these findings point to a marine-derived compound that reduces both inflammation and pyroptosis, representing a promising strategy for treating ulcerative colitis. Notably, these results come from preclinical studies and need further validation in clinical settings.