Ding-Zhi Xiao-Wan Decoction Ameliorates Poststroke Cognitive Impairment via Modulation of the Protein Kinase B/Glycogen Synthase Kinase 3 Beta/Mammalian Target of Rapamycin/Hypoxia-inducible Factor-1 Alpha Signaling Pathway: A Network Pharmacology an

Abstract Objective: Ding-Zhi Xiao-Wan decoction (DZXW), a traditional remedy for neurological disorders, shows potential in alleviating poststroke cognitive impairment (PSCI), yet its mechanisms remain unclear. Materials and Methods: This study aimed to elucidate DZXW’s therapeutic effects and molecular pathways in PSCI. Using network pharmacology, key bioactive compounds (kaempferol, 3,6’-disinapoyl sucrose, quercetin, pachymic acid, and 8-isopentenyl-kaempferol) were identified, targeting IL17-associated synaptic pathways and binding matrix metalloproteinase 2/amyloid precursor protein (MMP2/APP). Results: In a transient middle cerebral artery occlusion (tMCAO) mouse model, DZXW administration for 4 weeks improved cognitive function, as evidenced by Morris water maze, novel object recognition, and open-field tests. Histological analyses (H and E, Nissl staining, and transmission electron microscopy) revealed reduced neuronal damage and enhanced synaptic ultrastructure. Mechanistically, DZXW downregulated PSCI-related genes (APP, glycogen synthase kinase 3 beta (GSK3β), caspase-3, beta-secretase 1, MMP2/9) and serum inflammatory markers (MMP2, MMP9, and interleukin 17) via real-time quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and western blotting. Critically, DZXW-activated p-protein kinase B (Akt), p-mammalian target of rapamycin (mTOR), and hypoxia-inducible factor-1 alpha (HIF-1α) while inhibiting p-GSK3β, indicating modulation of the Akt/GSK3β/mTOR/HIF-1α axis. Conclusions: These results demonstrate that DZXW mitigates cognitive deficits by synergistically suppressing neuroinflammation, oxidative stress, and synaptic dysfunction through multi-target regulation. Our findings provide novel insights into DZXW’s neuroprotective mechanisms, positioning it as a promising therapeutic candidate for PSCI via pathway-specific intervention.