Li_2025_Nutrients_17_

BACKGROUND: Insect-derived proteins constitute an underutilized biological resource requiring urgent exploration to address global food protein shortages. However, their widespread application is hindered by the allergenic potential, particularly phospholipase A2 (PLA2), a highly immunoreactive allergen prevalent in edible insects such as ants and honeybees. OBJECTIVE: This study systematically investigated the molecular mechanism underlying quercetin-mediated reduction in PLA2 allergenicity, aiming to establish a novel strategy for developing hypoallergenic insect protein resources. METHODS AND RESULTS: Through integrated computational and experimental approaches, we identified quercetin's dual non-covalent and covalent binding capabilities with PLA2. Molecular docking revealed robust interactions (the binding energy of -6.49 kcal/mol) within the catalytic pocket. Meanwhile, mass spectrometry specifically identified Cys37 as the covalent modification site, which can bind to quercetin and increase the gyration radius (Rg) of PLA2 within 75-125 ns. Molecular dynamics simulations illustrated quercetin-induced conformational changes affecting critical antigenic epitopes. Murine experiments further confirmed that quercetin-modified PLA2 exhibited significantly reduced IgE reactivity and allergic responses compared to native PLA2, as demonstrated by assessments of anaphylactic behavior, histopathological changes, and measurements of serum IgE antibody and biogenic amine levels. CONCLUSIONS: Collectively, these findings provide a transformative approach to safely utilize insect-derived proteins for sustainable nutrition solutions.