Auranofin Ameliorates Gouty Inflammation by Suppressing NLRP3 Activation and Neutrophil Migration via the IL-33/ST2-CXCL1 Axis.

Gout is a form of sterile inflammatory arthritis in which monosodium urate (MSU) crystals deposit and provoke a neutrophil-predominant response, primarily driven by activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Here, we show that auranofin, a Food and Drug Administration (FDA)-approved anti-rheumatic agent, exerts anti-inflammatory effects in both in vitro and in vivo models of gout. Auranofin inhibited NLRP3 inflammasome activation in human THP-1 cells and murine macrophages, leading to reduced cleavage of caspase-1, interleukin-1β (IL-1β), and interleukin-18 (IL-18). In MSU crystal-induced mouse models, auranofin treatment reduced paw swelling, serum cytokine levels, and tissue inflammation. Notably, auranofin suppressed neutrophil migration and decreased expression of C-X-C motif chemokine ligand 1 (CXCL1) in inflamed foot tissue and air-pouch exudates. Mechanistically, auranofin disrupted the interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) axis, a key signaling pathway promoting neutrophil recruitment. Overexpression of IL-33 abolished the anti-inflammatory effects of auranofin, highlighting the central role of IL-33 in gout pathogenesis. Together, our findings suggest that auranofin alleviates MSU-induced inflammation by concurrently inhibiting NLRP3 inflammasome activation and IL-33-mediated neutrophil recruitment, supporting its potential as a dual-action therapeutic candidate for gout.