TH5487 specifically targets NLRP3 in FCAS patients resistant to MCC950

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 ability to inhibit NLRP3 activation in human cells. These compounds, including TH5487 (IC50 1.62 µM in human PBMCs), reduce IL-1β secretion while increasing type I interferon responses. Cryo-EM reveals direct association between NLRP3 and mitochondrial DNA, while structural modeling predicts interaction with oxDNA. Notably, inhibitors of the DNA repair glycosylase hOGG1 remain effective in L353P mutant PBMCs from FCAS patients and L351P in mice, at doses where the canonical NLRP3 inhibitor MCC950 is ineffective. Our findings uncover an additional druggable mechanism for inflammasome regulation via interference with oxidized DNA sensing, offering innovative therapeutic opportunities for autoinflammatory disease.