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. • SIRT1 suppresses NLRP3 inflammasome activation mainly at the activation phase. • Direct interaction of SIRT1 N-terminus with NLRP3 disrupts ASC oligomerization. • SIRT1 deacetylase activity is dispensable for inflammasome inhibition. • Findings reveal a novel therapeutic target via SIRT1–NLRP3 protein interaction.