摘要Nuclear factor erythroid 2-related factor 2(Nrf2),a master regulator of oxidative stress and inflam-masome,plays a critical role in modulating pyroptosis.In this study,we identified NU6300 as a novel small-molecule activator of Nrf2 that restores mitochondrial function,alleviates oxidative stress,and suppresses inflammasome activation and pyroptosis.Mechanistically,NU6300 covalently modified Kelch-like ECH-associated protein 1(Keap1)at cysteine-489,disrupting the Keap1-Nrf2 interaction,thereby promoting Nrf2 nuclear translocation and transcription of antioxidant genes.Notably,NU6300 inhibits NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome activation and gasdermin D(GSDMD)-mediated pyroptosis through redox-dependent mechanisms,representing the first evidence that covalent modification of Keap1 at cysteine-489 by NU6300 bridges Nrf2 activation and inflammasome suppression.In vivo,NU6300 exhibits potent antioxidant and anti-inflammatory protection against acetaminophen(APAP)-induced acute liver injury in mice.Collectively,these find-ings demonstrate that NU6300 is a novel Nrf2 activator and offers a promising therapeutic strategy for pyroptosis-driven inflammatory diseases.