Directly targeting G-quadruplexes contributes to the anti-multiple myeloma efficacy of Epimedokoreanin B

• Epimedokoreanin B (EKB) demonstrates potent anti-multiple myeloma activity with IC50 values of 5.28 μM and 6.81 μM against U266 and RPMI-8226 cell lines, respectively. • EKB specifically stabilizes G-quadruplex structures in oncogenes (c-Myc, c-KIT, Bcl-2, k-RAS), leading to downregulation of their expression in myeloma cells. • Computational analyses (molecular docking, MD simulations, MM/GBSA) reveal that EKB binds G4s via π-π stacking and hydrogen bonding, providing a mechanistic basis for its stabilizing effect. • This study positions EKB as a promising lead compound for targeting G-quadruplexes in multiple myeloma therapy, offering a novel strategy to overcome drug resistance.