Advances in Functional Mechanisms of Bioactive Peptides and Precision Nutrition Intervention Technologies

Bioactive peptides (BAPs) were characterized by diverse biological activities, high target specificity, favorable metabolic safety, and a wide range of sources, and were considered important functional components driving the transition from macronutrient supplementation toward precision interventions based on cellular signaling and metabolic networks. The forms, sources, and mechanisms of action of BAPs were systematically summarized. Exogenous BAPs derived from animals, plants, and microorganisms, as well as endogenous BAPs enriched in physiological samples, including serum, cerebrospinal fluid, milk, and gastrointestinal secretions were outlined. The molecular basis underlying the roles of BAPs in glucose and lipid metabolism, anti-aging effects, and intestinal barrier repair was elucidated. BAPs were shown to regulate the gut-pancreas axis through PepT1-, CaSR-, and GLP-1-related signaling and to ameliorate oxidative stress and glucose and lipid metabolic disorders through the ERK1/2/PI3K-Nrf2 and AMPK-ACC-SREBP-1c pathways. BAPs exerted anti-aging effects by remodeling the microbiota-gut-brain axis, promoting the enrichment of beneficial microorganisms and the production of short-chain fatty acids, suppressing neuroinflammation, and maintaining mitochondrial homeostasis. In addition, BAPs inhibited inflammation and reinforced tight junctions through the Nupr1-autophagy-mitochondrial axis and the JAK-STAT and MAPK pathways. Additional functions of BAPs in blood pressure regulation, oxidative stress resistance, and immune modulation were also summarized. Furthermore, three key technological systems that facilitated BAP-based precision interventions were reviewed, including targeted discovery based on data-independent acquisition peptidomics, artificial intelligence, structural prediction, and molecular dynamics simulations; screening and structural optimization centered on phage display, solid-phase peptide synthesis, peptide stapling, and D-amino acid incorporation; and functional evaluation and mechanistic validation integrating organoids, three-dimensional culture, CRISPR-Cas9 gene editing, and multilevel animal models. On this basis, a full-chain research and development framework comprising “sequence mining-structural optimization-systematic validation-in vivo response” was proposed. Efficient delivery, elucidation of in vivo metabolic mechanisms, and interindividual variability in responses were identified as persistent barriers to translation. This review aimed to provide theoretical and technical support for the development of highly bioactive foods for special medical purposes, medical nutrition formulations, and functional foods, as well as for the early prevention of chronic diseases and precision nutritional intervention.