Abstract

Background Ziziphora clinopodioides Lam. ( Z. clinopodioides ), a distinctive medicinal plant endemic to Xinjiang, is predominantly centers on cardiovascular diseases. However, its possible therapeutic value in neurologic conditions have not been thoroughly examined, especially in Alzheimer's disease (AD). Purpose This study elucidates the intervention effect and mechanism of Z. clinopodioides on cognitive dysfunction in vivo and in vitro. Methods UPLC-Q-Exactive-HR MS/MS technology was employed to analysis the chemical components of Z. clinopodioides and that enter into the serum and brain. the extract of Z. clinopodioides and linarin were administered orally to 3 × Tg-AD mice. Behavioral assessments were carried out and AD-pathology indicator were detected. Additionally, network pharmacology and non-target metabolomics were combined to analyze the potential mechanism. Results Flavonoids from Z. clinopodioides (ZCF) were identified as the main components, with linarin being the most abundant. ZCF and linarin improved spatial memory, reduced Aβ deposition and Tau phosphorylation, and suppressed glial cell activation. Mechanistically, ZCF and linarin decreased NLRP3 protein levels and NF-κB phosphorylation, while enhancing LC3B, p62, and Cathepsin D expression, resulting in reduced IL-1β and IL-18 secretion in 3 × Tg mice, HT22 cells or BV2 cells—effects reversed by autophagy inhibition. ZCF promoted NLRP3 and p62 co-localization, leading to NLRP3 degradation via autophagy without affecting its mRNA levels. Conclusion ZCF restores the autophagy-lysosome pathway and suppresses NLRP3 inflammasome activation, significantly improving cognitive dysfunction in 3 × Tg-AD mice, and highlighting ZCF or linarin as promising candidates for AD treatment.