Network Pharmacology Framework Characterizes Polypharmacological Properties of Dietary Flavonoids: Integration of Computational, Experimental, and Epidemiological Evidence

Dietary flavonoids associate with disease prevention in epidemiological studies, yet their polypharmacological mechanisms remain unclear. We establish network pharmacology as a systematic framework to characterize flavonoid therapeutic properties through integrated computational, experimental, and epidemiological validation. We constructed a master network of 17,869 human proteins, 14 dietary flavonoids, and 1,496 FDA-approved drugs with 278,768 interactions. Flavonoids averaged 45.3 target proteins per compound compared to 16.8 for FDA-approved drugs (2.7-fold higher; p=7.5x10^-4), reflecting multi-target architecture. Statistical analysis revealed that 71.4% of flavonoids targeted proteins associated with cardiovascular drugs and 78.6% aligned with antineoplastic drug targets. MTT-based Jurkat cell assays confirmed network predictions: high-association flavonoids (luteolin LC50=31.4 microM, myricetin=29.5 microM) produced strong cytotoxicity, while low-association flavonoids showed minimal activity (LC50>200 microM). Network-predicted association strengths correlated with experimental bioactivity (Pearson r=0.918; R^2=0.843). We translated network associations into food-level predictions across 506 foods, identifying 685 food-drug therapeutic combinations. Systematic literature searches confirmed 96 associations supported by 132 unique references. Cardiovascular domains achieved 47.1% validation. Top-validated foods included tea (31 evidence items), blueberries (18 items), tomato (13 items), grape juice (10 items), and plum (9 items). Network pharmacology characterizes dietary polypharmacological properties and generates evidence-based food-therapeutic predictions, bridging nutritional science and systems pharmacology.

Source: arXiv:2601.08147v1 - http://arxiv.org/abs/2601.08147v1 PDF: https://arxiv.org/pdf/2601.08147v1 Original Link: http://arxiv.org/abs/2601.08147v1