Abstract
Plant-derived bioactive peptides have been suggested as a class of compounds with neuroprotective properties. This study focused on the cognitive-enhancing effects of Cyperus esculentus peptide (CEP) based on ‘in silico-drosophila-mice’ stepwise cognitive impairment models, followed by systematical elucidation in multi-target mechanism of its function. Specifically, network pharmacology prediction indicated that CEP exerted the modifying effects through essential nodes including cAMP signaling pathways and neuroinflammation regulation. Behavioral experiments confirmed that CEP effectively enhanced learning and memory capability of stress-modeled fruit flies and scopolamine-induced cognitive impairment mice. Then, mechanism investigation indicated that CEP could activate the cAMP-PKA-CREB-BDNF signaling axis within the central nervous system, enhancing synaptic plasticity (upregulated PSD-95 expression) while concurrently alleviating oxidative stress, cholinergic imbalance, and neuroinflammation. Additionally, CEP remodeled gut microbiota ecology, increasing beneficial bacteria abundance such as Akkermansia and Bifidobacterium and substantially enhancing short-chain fatty acid (SCFA) production. This further activated FFAR2/3 receptor signaling, restored intestinal barrier integrity and suppressed peripheral inflammation, indicating a neuroprotective pathway via the microbiota-gut-brain axis. Conclusively, this study confirmed CEP as a highly promising cognitive enhancer in a synergistic mode of coordinated regulation of central nervous and peripheral pathways, which provided theoretical underpinnings for intervention strategies of bioactive peptides in Cyperus esculentus targeting neurodegenerative diseases via the gut-brain axis.