Insights into osteoporosis triggered by common antiepileptic drugs via network toxicology, molecular docking and molecular dynamics simulations.

Background: Antiepileptic drugs (AEDs), first-line treatments for epilepsy and related seizure disorders, are increasingly recognized as important risk factors for osteoporosis. However, the molecular mechanisms and specific targets underlying AED-induced bone loss remain largely unclear. Methods: We explored these mechanisms using an integrated strategy combining network toxicology, molecular docking, molecular dynamics simulations, and Results: We identified 47, 50, 46, and 48 potential osteoporosis-related targets for carbamazepine phenobarbital phenytoin (PHT), and valproic acid respectively. These targets were mainly enriched in key signaling pathways and cellular processes associated with bone metabolism. Topological analysis identified four primary hub targets: epidermal growth factor receptor, CASP3, peroxisome proliferator-activated receptor gamma, and PTGS2. AEDs and their targets exhibited favorable binding affinity in the molecular docking simulations (binding energy < -5 kcal/mol). Molecular dynamics simulations revealed heterogeneous dynamic stability among the complexes: PB-CASP3 and PHT-PPARG reached relatively stable conformational equilibrium, whereas CBZ-EGFR displayed notable protein residue flexibility in the equilibrated trajectory, and VPA-PTGS2 sustained persistent structural fluctuations during the simulation period. Conclusion: This study constructs an integrated research framework combining computational prediction and