Identification and Mechanistic Study of a Novel Keap1-Targeting Antioxidant Peptide From Ulva prolifera Protein

Activating Nrf2 by targeting the Keap1-Nrf2 signaling axis has emerged as a viable therapeutic approach for managing oxidative stress and its associated disorders. This study employed virtual digestion, ADMET profiling, and molecular docking to identify antioxidant peptides derived from Ulva prolifera protein. A novel tetrapeptide (WDGL) was ultimately discovered, demonstrating favorable aqueous solubility, non-toxicity, high intestinal absorption efficiency, and blood-brain barrier permeability. WDGL established four H-bond interactions with some key sites of Keap1 (Arg380, Arg415, Ile416, Leu365). Besides, WDGL reduces ABTS·⁺ and ferric-tripyridyltriazine (Fe³⁺-TPTZ) in vitro and promotes the expression of GSH-Px while increasing GSH-Px and SOD enzyme activity to eliminate ROS in LPS-treated EA.hy926 cells. Furthermore, this peptide could reduce the content of ROS and ET-1 in Ang II-induced EA.hy926 cells. The result suggested that WDGL may alleviate EA.hy926 oxidative damage by activating the Keap1-Nrf2 signaling pathway.