Ultrasound-assisted extraction of total flavonoids from Epimedium brevicornu maxim with ionic liquids: Optimization and mechanistic insight

• A systematic "theory-to-experiment" paradigm integrating COSMO-RS, RSM, and molecular simulation is established for rational design of ionic liquid extraction systems. • [C₃mim]Cl is identified as the optimal solvent, achieving a total flavonoid yield of 8.15 ± 0.13 mg/g - outperforming conventional ethanol reflux by 9.7% with 77% less extraction time. • Multi-scale mechanistic studies (DFT/MD) reveal that synergistic hydrogen bonding, π-π stacking, and electronic interactions drive the enhanced extraction efficiency. • The recyclability of [C₃mim]Cl was demonstrated, and AGREE assessment confirmed its greener profile (0.66 vs. 0.27), supporting its potential as a sustainable alternative for natural product extraction.