Isolation, identification and in silico analysis of two novel cytoprotective peptides from tilapia skin against oxidative stress-induced ovarian granulosa cell damage

[Display omitted] •Two novel cytoprotective peptides from tilapia skin were identified by LC-MS/MS.•APDPFRMY and NGGPDWAR significantly alleviate ovarian granulosa cell damage.•These cytoprotective peptides are expected to be used as nutraceuticals additives.•A new idea for isolating and identifying food-borne bioactive peptides. The high-value-added substances in tilapia (Oreochromis mossambicus) skin have not been fully utilized, and the demand for novel food-derived bioactive peptides is increasing. Here, the cytoprotective peptides in the tilapia skin enzymatic hydrolyzate were isolated and identified. In addition, novel peptides with potential high biological activity (APDPFRMY and NGGPDWAR) were screened by a computer virtual screening strategy for artificial synthesis, and the cytoprotective activity was verified by the oxidative stress-induced ovarian granulosa cell model. Meanwhile, molecular docking and western blot results showed that two novel cytoprotective peptides could interact with critical residues of the Kelch domain of Keap1 through hydrogen bonding, electrostatic interactions, and hydrophobic interactions. Moreover, APDPFRMY and NGGPDWAR could partially occupy the binding sites of Nrf2 and Keap1, thus playing a role in protecting cells from oxidative damage. This study also provides a new idea for isolating and identifying food-derived bioactive peptides.