Walnut-derived peptide mitigates bisphenol AF-induced neurotoxicity in zebrafish: behavioral improvement associated with Cav1/AMPK-PI3K/Akt signaling

Walnut is a nutrient-rich food resource, yet the utilization of its high-quality plant proteins remains inefficient. Advanced processing strategies are therefore needed to develop walnut-based functional foods. In this study, walnut peptides were prepared by sequential hydrolysis with alcalase and papain, leading to the identification of a novel antioxidant peptide, IRALPEEVL. In vitro , IRALPEEVL increased the viability of PC12 cells under H 2 O 2 -induced oxidative stress. In vivo , it ameliorated cognitive and memory dysfunctions in zebrafish exposed to the environmental toxicant bisphenol AF. Proteomic analysis indicated that the neuroprotective effects of IRALPEEVL were associated with caveolin-1 (Cav1)-dependent penetration of the blood-brain barrier, regulating the AMPK-PI3K/Akt signaling, and inhibiting neuronal apoptosis. These findings highlight the potential of value-added walnut processing and support the application of walnut-derived peptides as functional food ingredients for health promotion. • Walnut-derived peptide IRALPEEVL exhibits antioxidant activity. • IRALPEEVL ameliorates cognitive and memory dysfunction in zebrafish. • IRALPEEVL inhibits apoptosis and reduces neuron loss via AMPK-PI3K/Akt signaling. • IRALPEEVL penetrates the blood-brain barrier via Cav1 and exerts neuroprotective effects.