Ciclopirox Olamine Inhibits the NLRP3 Inflammasome to Alleviate Inflammatory Diseases

The aberrant activation of the NOD-like receptor protein 3 (NLRP3) inflammasome has been implicated in the pathogenesis of various human inflammatory diseases. Although a wide variety of NLRP3 inflammasome inhibitors have been developed, no drug targeting the NLRP3 inflammasome has been approved for use in clinical settings. In this study, we identified ciclopirox olamine (CPX), an antifungal agent approved by the US Food and Drug Administration (FDA), as a novel NLRP3 inflammasome inhibitor. CPX specifically blocks NLRP3 inflammasome activation but not AIM2, NLRC4, Pyrin, NLRP1, or NLRP6 inflammasomes. Mechanistically, CPX directly disturbs NLRP3 inflammasome assembly by inhibiting NLRP3 oligomerization. Furthermore, CPX binds to the NACHT domain of NLRP3 at Y381 and reduces NLRP3 ATPase activity, thereby blocking NLRP3 oligomerization. More importantly, CPX administration notably exerts therapeutic effects on mouse models of sepsis, colitis, and metabolic disorders. CPX is also active ex vivo in cells from healthy individuals or patients with gout. Taken together, our results demonstrate that CPX acts as an NLRP3 inflammasome inhibitor and is a promising therapeutic agent for NLRP3 inflammasome-associated diseases.