Fruit‐Derived <i>Citri Reticulatae</i> Semen Extract Attenuates Alzheimer's Disease Neuroinflammation and Cognitive Impairment via Modulation of the PI3K/Akt/FoxO1 Pathway

stimulated BV-2 microglia, 3×Tg-AD mice, and Tg (apoeb: lynEGFP) zebrafish larvae. We found that CRSE significantly suppressed Aβ-induced microglial activation, NLRP3 inflammasome signaling, and pro-inflammatory cytokine release in BV-2 cells. In 3×Tg-AD mice, CRSE supplementation improved spatial learning and memory, reduced hippocampal glial reactivity and neuronal loss, and attenuated tau pathology and NLRP3/ASC/Caspase-1 activation. It also reduced microglial activation in zebrafish. Integrated transcriptomics and network pharmacology analyses converged on the PI3K/Akt/FoxO1 axis. Subsequent validation demonstrated that CRSE restored Aβ-impaired phosphorylation of PI3K, Akt, and FoxO1, and its anti-inflammatory effects were attenuated by the PI3K inhibitor. Collectively, these findings demonstrate that the fruit-derived CRSE ameliorates AD-related pathology by modulating the PI3K/Akt/FoxO1 pathway and suppressing NLRP3 inflammasome activation. This study provides a mechanistic basis for considering CRSE as a botanical candidate for dietary interventions aimed at neuroprotection in AD.