Gastrodenol suppresses NLRP3/GSDMD mediated pyroptosis and ameliorates inflammatory diseases

Abstract

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.