Cepharanthine inhibits NLRP3 inflammasome-induced pyroptosis through ARIH2-mediated degradation of NLRP3.

Cepharanthine (CEP), a bioactive alkaloid isolated from Stephania cepharantha Hayata, has been reported to exhibit a range of pharmacological activities, including anti-inflammatory, antiviral, and anti-cancer effects. Pyroptosis is a form of programmed cell death mediated by the inflammasome-caspase-gasdermin signalling cascade. However, the anti-pyroptotic effects of CEP and their underlying molecular mechanisms remain largely unknown. In this study, CEP was found to inhibit NLRP3 inflammasome-mediated pyroptosis specifically by promoting polyubiquitination and subsequent degradation of NLRP3. This process was mediated by the E3 ubiquitin ligase ARIH2, which was recruited through the direct interaction between CEP and NLRP3, thereby facilitating ARIH2-mediated assembly of K48-linked ubiquitin chains on NLRP3. Consequently, CEP potently suppressed NLRP3 inflammasome activation and mitigated systemic inflammation in lipopolysaccharide (LPS)-challenged mice, while having no effect on NLRC4-dependent peritonitis induced by Salmonella typhimurium in vivo. In conclusion, these findings emphasise the anti-pyroptotic properties of CEP and suggest that it could be an effective treatment for NLRP3-driven inflammatory diseases.