CommsBio_2025

Aberrant activation of the NLRP3 inflammasome contributes to a wide range of chronic inflammatory disorders. Here, we investigate small-molecule inhibitors originally developed to target the DNA repair enzyme hOGG1 and demonstrate their unexpected ability to inhibit NLRP3 activation. These compounds, including TH5487 (IC50 1.62 µM in human PBMCs), reduce IL-1β secretion while increasing type I interferon responses. CryoEM and computational analyses reveal a direct association between NLRP3 and oxDNA. Notably, glycosylase inhibitors remain effective in L353P mutant PBMCs from Familial Cold Autoinflammatory Syndrome (FCAS) patients and L351P in mice, at doses where the canonical NLRP3 inhibitor MCC950 is ineffective. Our findings uncover a novel, druggable mechanism for inflammasome regulation via interference with oxidized DNA sensing, offering new therapeutic opportunities for autoinflammatory disease.