Abstract:Excessive activation of the NOD-like receptor pyrin domain–containing protein 3 (NLRP3) inflammasome plays a key role in the pathogenesis of various inflammatory diseases. Despite the development of several NLRP3 inhibitors, no specific therapy has been approved for clinical use, underscoring the urgent need for safe and effective agents. Here, we demonstrate that ML345 acts as a highly potent and selective NLRP3 inhibitor with strong therapeutic potential for NLRP3-driven inflammation. ML345 effectively suppresses canonical, noncanonical, and alternative NLRP3 inflammasome activation pathways, without affecting other inflammasomes. Mechanistically, ML345 blocks NLRP3 inflammasome activation independently of its intrinsic insulin-degrading enzyme (IDE) inhibitory activity. ML345 binds to NLRP3 in a non-covalent manner and directly targets tyrosine 381 (Y381), disrupting its essential interaction with NIMA-related kinase 7 (NEK7), consequently preventing inflammasome complex formation. In vivo, ML345 is well tolerated and markedly alleviates inflammatory responses and pathology in mouse models of NLRP3-associated disorders, including systemic inflammation and miscarriage triggered by lipopolysaccharide (LPS). Compared with several previously reported NLRP3 inhibitors, ML345 exhibits superior selectivity and comparable or greater inhibitory potency. These findings establish ML345 as a safe and selective NLRP3 inhibitor with robust anti-inflammasome effects and highlight its potential as a promising therapeutic candidate for NLRP3-driven diseases.
