Repurposing Simvastatin and Lovastatin for Colorectal Cancer: An Integrated in-Silico and in-Vitro Study

Background Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Statins, widely prescribed lipid-lowering agents, have been suggested to possess anticancer activity; however, their precise mechanisms in CRC remain poorly defined. Methods This study employed an integrated in silico–in vitro approach to investigate the therapeutic potential of Simvastatin and Lovastatin in CRC. Network pharmacology analysis identified hub genes linking the mevalonate pathway, lipid biosynthesis, and apoptosis regulation. Molecular docking was performed to assess binding affinities, followed by molecular dynamics (MD) simulations and MM-PBSA free energy calculations for stability and binding strength evaluation. In vitro cytotoxicity was validated using HCT116 and HT-29 colorectal cancer cell lines. Results Five hub genes (HMGCR, CYP51A1, FDFT1, SCD, and LCK) were identified as key targets. Docking studies revealed strong binding affinities, with scores of −8.4 kcal·mol −1 for Simvastatin–3LCK, −9.5 kcal·mol −1 for Lovastatin–3WEG, and −9.4 kcal·mol −1 for Lovastatin–8SBI complexes. MD simulations indicated stable binding of Simvastatin with 3LCK, characterized by minimal RMSD and SASA fluctuations, whereas Lovastatin displayed higher flexibility. MM-PBSA analysis demonstrated robust binding free energies for Lovastatin–3WEG (–64.73 kcal·mol −1 ) and Simvastatin–3LCK (–56.47 kcal·mol −1 ). In vitro assays confirmed a dose-dependent reduction in cell viability, with IC 50 values of 8.9 ± 0.17 μM (Simvastatin) and 12.6 ± 0.32 μM (Lovastatin) in HCT116, compared with 14.4 ± 0.15 μM and 18.7 ± 0.53 μM in HT-29 cells, respectively. Conclusion This integrated study demonstrates that Simvastatin and Lovastatin exert cytotoxic effects in CRC cells by targeting metabolic and apoptotic pathways. Simvastatin showed superior activity compared with Lovastatin.