Epigallocatechin gallate inhibits Enterovirus 71 infection by modulating environmental information processing: systems biology and molecular simulation insights.

Enterovirus 71 (EV71) is a major causative agent of hand, foot, and mouth disease, yet specific antiviral therapies remain unavailable. This study aimed to elucidate the molecular mechanisms of (-)-Epigallocatechin-3-gallate (EGCG) against EV71 and assess its therapeutic translational potential through integrated systems biology analyses, computational modeling, and experimental validation. EGCG was prioritized over other polyphenols due to the unique structural contribution of its galloyl groups, which conferred a 2.7-fold increase in stability when binding to EV71 3C protease compared to reference ligands. Multi-omics analyses identified 2799 EGCG-related targets converging on the NF-κB pathway, with CXCR4 and CXCL10 highlighted as key regulatory hubs. Molecular dynamics revealed stable conformations (RMSD <2 Å), and in vitro studies demonstrated dose-dependent viral inhibition (IC50 = 12.3 μM) via NF-κB suppression, with preventive administration achieving 87 % cell viability. In vivo results confirmed modulation of the TLR2/p65 axis, although optimal clinical bioavailability remains a major challenge. Notably, unresolved questions persist regarding the dynamic binding plasticity of EGCG to EV71 capsid rearrangements and effective oral delivery. These findings collectively establish preclinical proof of concept for an EGCG-based intervention against EV71 while highlighting critical gaps and underscoring the need for formulation strategies to facilitate clinical translation.