CHK1 phosphorylates TRIM28 at Ser473 to drive NLRP3 inflammasome assembly and inflammatory responses.

The NLRP3 inflammasome is a central player in innate immunity and is implicated in various inflammatory diseases, but its kinase-mediated regulatory networks remain incompletely defined. Here, we identify CHK1 as a positive regulator of NLRP3 inflammasome activation. Pharmacological inhibition or siRNA-mediated knockdown of CHK1 suppressed NLRP3-dependent caspase-1 activation, IL-1β secretion, and pyroptosis, without affecting AIM2 or NLRC4 inflammasomes. CHK1 promoted NLRP3 oligomerization and ASC speck formation in a kinase activity-dependent manner. Mechanistically, CHK1 phosphorylated the E3 SUMO ligase TRIM28 at Ser473. This phosphorylation enhanced NLRP3 protein stability and SUMOylation. CHK1 inhibition alleviated LPS-induced systemic inflammation in vivo. Our findings reveal a CHK1-TRIM28 axis that selectively drives NLRP3 inflammasome activation and suggest CHK1 as a potential therapeutic target for NLRP3-driven pathologies.