BACKGROUND: Cognitive impairment is a common feature of neurodegenerative diseases, in which sustained neuroinflammation critically contributes to neuronal dysfunction and memory decline. As a representative condition, Alzheimer's disease (AD) provides key insights into inflammation-associated cognitive impairment. However, current anti-inflammatory interventions exhibit limited efficacy and potential adverse effects, highlighting the need for safer strategies targeting neuroinflammation-related cognitive dysfunction. OBJECTIVE: Guided by the concept of food-medicine homology, this study aimed to elucidate the molecular mechanisms by which Ziziphus jujuba alleviates cognitive impairment associated with neuroinflammation. METHODS: AD-relevant targets associated with cognitive dysfunction were obtained from Gene Expression Omnibus (GEO) and GeneCards, and active compounds of Z. jujuba were retrieved from traditional Chinese medicine systems pharmacology (TCMSP). Shared targets were prioritized using least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machine (SVM) algorithms. The diagnostic value of the core target was evaluated by receiver operating characteristic (ROC) analysis and a nomogram model with calibration and decision curve analysis (DCA). Functional enrichment, localization analyses, and molecular docking were performed. Experimental validation was conducted in a scopolamine-induced cognitive impairment mouse model using the Morris water maze (MWM), histopathology, and western blotting. RESULTS: PTGS2 was identified as a key inflammatory target associated with neuroinflammation-related cognitive impairment and was enriched in the NOD-like receptor (NLR) signaling pathway. ROC and nomogram analyses indicated good diagnostic and predictive performance (area under the curve AUC > 0.7). PTGS2 was localized on chromosome 1 and showed relatively high expression in the cerebral cortex. Z. jujuba compounds exhibited strong binding to PTGS2 (ΔG ≤ -8.0 kcal/mol). In vivo, Z. jujuba improved cognitive performance, alleviated hippocampal injury, and downregulated PTGS2 and related inflammatory signaling pathways, including NLRP3/NF-κB/MAPK and interleukin (IL)-1β. CONCLUSION: This study demonstrates that Z. jujuba ameliorates neuroinflammation-related cognitive dysfunction primarily by suppressing PTGS2-centered inflammatory signaling. Integrating computational analyses and in vivo validation in scopolamine-induced mice, our findings support Z. jujuba as a safe multitarget intervention for inflammation-associated cognitive impairment and highlight the potential of food-medicine homology in neuroinflammatory cognitive disorders.
Liu et al. (Thu,) studied this question.