Acacetin targets SNX5 to promote autophagy degradation of NLRP3 inflammasome against cognitive impairment in Alzheimer's disease

Alzheimer's disease (AD) is a chronic, low-grade inflammatory neurodegenerative disorder. Inhibiting the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a potential therapeutic strategy for AD, but no approved NLRP3-specific inhibitors are available for clinical use, and current agents often cause significant side effects despite their anti-inflammatory benefits. Acacetin, is a flavonoid compound that can penetrate the blood-brain barrier, with potential for treating AD.The purpose of this study is to clarify the relationship between the anti-AD effect of acacetin and its mechanism of inhibiting NLRP3. Acacetin improved cognitive function and reduced neuronal damage in 3xTg mice. Further Acacetin directly binds to sorting nexin-5 (SNX5) and upregulates its expression. This, in turn, activates Autophagy to degrade the NLRP3 inflammasome, alleviates inflammationin HT-22 cells and BV-2 cells. These findings suggest that Acacetin can exert an anti-AD effect by targeting SNX5 to activate Autophagy and promote the degradation of the NLRP3 inflammasome, which underscore the importance of targeting SNX5 to suppress NLRP3 inflammasome activation in AD treatment.