Exploring the structure–activity relationships and molecular mechanisms of food-derived antioxidative peptides in mitigating oxidative stress: A comprehensive review

Oxidative stress is mainly attributed to the overproduction of reactive oxygen or nitrogen species during mitochondrial electron transport chain reactions. The presence of these reactive species correlates with metabolic conditions, including inflammation, aging, and neurodegeneration. Food-derived bioactive peptides exhibit antioxidative abilities potentially dependent on processing conditions and structural characteristics, including molecular weight and amino acid sequences. This review summarizes recent advances in generating food protein-derived antioxidant peptides and comprehensively explores comparative structural characterization as the basis for examining the molecular mechanisms underlying anti-oxidative potential in mammalian cells. Enzymatically produced antioxidant peptides with molecular weight ˂3 kDa and short amino acid sequences typically exhibit enhanced intestinal epithelial membrane permeability via enterocytes, tight junctions, and passive diffusion, exerting antioxidative potential. Their antioxidative potential is associated with decreased intracellular reactive oxygen species and malondialdehyde production. Additionally, they enhance the defense capabilities of enzymatic (superoxide dismutase and catalase) and non-enzymatic antioxidants (ascorbic acid and alpha-tocopherol). Mechanistically, they regulate major oxidative protein pathways, including Keap1-Nrf2-ARE, MAPK, NF-κB, and PI3K/AKT/mTOR. Intriguingly, plants and animal-derived peptides exhibit different structural characteristics. Plant-derived peptides tend to be negatively charged, making them more soluble with greater bioavailability. Future researchers should focus on developing new technologies for large-scale commercial production of food protein-derived antioxidant peptides and verifying their health benefits in vivo while addressing limitations and safety considerations. Graphical abstract for the systematic flow of conventional and in-silico bioactive peptide preparation, isolation, purification, identification, and antioxidant potential evaluation. • Food-derived bioactive peptides serve as natural sources to mitigate oxidative stress. • These peptides' structure and antioxidant capacity were analyzed using conventional and in-silico approaches. • Plant-derived peptides often demonstrate excellent solubility and bioactivity. • Peptides regulate endogenous antioxidants and key oxidative stress pathways such as Keap1-Nrf2-ARE, NF-κB, MAPK, and PI3K/AKT/mTOR.