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Abstract

Mounting evidence indicates that NLRP3 inflammasome-mediated pyroptosis is critically involved in Parkinson’s disease (PD) pathogenesis. Sinomenine (SN) possesses neuroprotective properties and is known to modulate the NLRP3 inflammasome, but its potential to protect against PD via pyroptosis inhibition remains unexplored. This study demonstrates that SN confers significant neuroprotection in both cellular and animal PD models. Key findings show that SN alleviates motor deficits and nigral pathology in vivo, enhances neuronal viability, and suppresses pyroptosis in vitro. Mechanistically, SN potently inhibits NLRP3 inflammasome activation and subsequent cleavage of Caspase-1 and GSDMD, reducing levels of IL-1β and IL-18. The enhanced protection observed with the NLRP3 inhibitor MCC950 co-treatment validates the involvement of this pathway. Our results establish that SN mitigates PD-associated damage primarily by targeting the NLRP3/Caspase-1/GSDMD-mediated pyroptotic pathway. Graphical