Icariside II attenuates renal fibrosis through mTOR signaling modulation: an integrated approach combining network pharmacology, molecular dynamics, and

Background: Renal fibrosis (RF), the end-stage progression of chronic kidney disease (CKD), remains a challenge due to limited effective therapies. Icariside II (ICA-II), a metabolite of icariin from the Chinese herb Epimedium, has shown therapeutic promise in treating diabetic CKD. However, the underlying molecular mechanisms remain elusive. This study sought to elucidate these mechanisms using an integrated approach: network pharmacology, molecular dynamics (MD) simulations, and Methods: Network pharmacology was integrated with public databases to identify ICA-II targets and RF-associated genes. Key targets were prioritized using protein-protein interaction (PPI) networks. Molecular docking and MD simulations assessed ICA-II-target interactions. Results: Network pharmacology revealed ten key targets: AKT1, mTOR, EGFR, ESR1, BCL2, CASP3, TP53, CTNNB1, HSP90AA1, and HSP90AB1. Critical pathways included PI3K/Akt/mTOR, lipid and atherosclerosis, and EGFR tyrosine kinase inhibitor resistance. Molecular docking showed stable ICA-II binding to mTOR (docking energy: -12 kcal/mol), confirmed by MD simulations over 100 ns. Conclusions: ICA-II demonstrates anti-fibrotic effects through a multi-target, multi-pathway regulatory network. Its beneficial role in RF may involve direct inhibition of mTOR activity, thereby attenuating excessive extracellular matrix (ECM) accumulation. These findings provide a theoretical and experimental basis for ICA-II as a promising candidate for the treatment of RF.