Gastrodenol suppresses NLRP3/GSDMD mediated pyroptosis and ameliorates inflammatory diseases

Abstract Pyroptosis, a form of inflammatory programmed cell death, plays a pivotal role in the pathogenesis of various diseases. This process is primarily mediated by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3). Gastrodenol (Bismuth tripotassium dicitrate, GAS) is a mineral compound which is used to treat duodenal and gastric ulcers associated with Helicobacter pylori . In this study, GAS was found to exhibit protective effects against classical pyroptosis in macrophages. Specifically, GAS effectively inhibits the activation of the NLRP3 inflammasome, Gasdermin D (GSDMD)-mediated pyroptosis, and the secretion of pro-inflammatory cytokines. Mechanistically, GAS inhibited NLRP3 oligomerization and reduced the oligomerization of adaptor protein apoptosis-associated speck like protein containing a caspase activation and recruitment domain (ASC). In mouse models, GAS treatment demonstrated remarkable attenuation of pyroptosis-mediated inflammatory diseases, including experimental autoimmune encephalomyelitis (EAE) model, lipopolysaccharide (LPS)-induced septic mice, and monosodium urate (MSU)-induced peritonitis. These findings collectively establish GAS as a potent inhibitor of pyroptosis and propose a novel therapeutic strategy for the prevention and treatment of NLRP3-GSDMD mediated diseases.