Sirtuin 1 inhibits NLRP3 inflammasome activation through protein-protein interaction

Sirtuin 1 (SIRT1) is known to suppress NLRP3 inflammasome activation via NF-κB inhibition, but its role in inflammasome assembly remains unclear. Here, using a HEK293T reconstitution system, we show that SIRT1 directly interacts and co-localizes with NLRP3 upon inflammasome activation. SIRT1 co-expression disrupts NLRP3-ASC interaction and NLRP3-dependent ASC oligomerization, thereby impairing inflammasome assembly. Co-immunoprecipitation analyses reveal that the N-terminus of SIRT1 is essential for binding and inhibitory function, whereas its deacetylase activity is dispensable. These findings highlight that SIRT1 suppresses NLRP3 inflammasome activation primarily through protein-protein interaction rather than deacetylation, suggesting a potential basis for targeting NLRP3-SIRT1 interaction in inflammasome-related diseases.