Mongkolnkrajang U.Kuptawach K.Sangtanoo P.Saisavoey T.Boonserm P.Reamtong O.Srimongkol P.Karnchanatat A.Mahidol University2026-03-032026-03-032026-12-01Scientific Reports Vol.16 No.1 (2026)https://repository.li.mahidol.ac.th/handle/123456789/115517This study investigates the potential of bee pollen protein hydrolysate (BPPH) as a natural source of bioactive peptides capable of inhibiting dipeptidyl peptidase IV (DPP-IV) for the management of type 2 diabetes mellitus (T2DM), a metabolic disorder characterized by insulin resistance and hyperglycemia. BPPH was generated through pepsin–pancreatin digestion, followed by ultrafiltration and RP-HPLC purification. LC-Q-TOF-MS/MS analysis identified Ala-Thr-His-Ala-Leu-Leu-Ala (ATHALLA, AA-7) as a predominant peptide associated with DPP-IV inhibitory activity. AA-7 exhibited strong DPP-IV inhibitory activity (IC<inf>50</inf> = 52.63 ± 2.32 µM) relative to the reference inhibitor diprotin A (IC<inf>50</inf> = 22.4 ± 1.29 µM). Molecular docking predicted stable binding of AA-7 within the DPP-IV catalytic pocket, mediated by hydrogen bonding and hydrophobic interactions with key residues. AA-7 also modulated glucose uptake in Caco-2 cells, influencing SGLT1 and GLUT2 gene expression in a dose-dependent manner. Docking analysis suggested potential interactions with selected SGLT1 and GLUT2 residues, providing structural support for the observed cellular responses rather than definitive mechanistic evidence. In silico ADMET analysis indicated poor passive membrane permeability and limited predicted intestinal absorption, along with minimal CYP450 interactions and low predicted toxicity, highlighting potential pharmacokinetic limitations while supporting a favorable safety profile. These findings highlight AA-7 as a dual-action peptide with demonstrated DPP-IV inhibitory activity and the ability to modulate glucose transport in vitro, supporting the potential of bee-pollen-derived peptides for glycemic regulation and functional food or nutraceutical applications.MultidisciplinaryArticleSCOPUS10.1038/s41598-026-39009-12-s2.0-10503116538220452322