Targeting of NLRP3 Gln624/Ser658 by Carabrone attenuates inflammatory diseases.

Abstract

The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in host defense; however, its aberrant activation leads to excessive release of pro-inflammatory cytokines, triggering inflammatory responses and tissue damage in human diseases. In this study, the inhibitory effect and anti-inflammatory potential of carabrone on the NLRP3 inflammasome were systematically evaluated. Carabrone suppressed lipopolysaccharide (LPS) + ATP/Nigericin-induced IL-1β secretion, Caspase-1 activation, and apoptosis-associated speck-like protein (ASC) speck formation. Mechanistic investigations revealed that carabrone inhibited the NLRP3-NEK7 interaction and bound to Gln 624 and Ser 658 within the NACHT domain of NLRP3, thereby stabilizing the local conformation and inhibiting inflammasome activation. In addition, carabrone showed protective effects in Alzheimer's disease (AD) models, which were associated with NLRP3 inflammasome inhibition. Similar effects were also observed in other NLRP3 inflammasome-related disease models, including sepsis, gouty arthritis, and acute peritonitis. Collectively, these results indicate that carabrone might act as a modulator of NLRP3 inflammasome activation across multiple inflammatory disease contexts.