Insights into the Mechanistic Actions of Vitamin D3 in Colorectal Cancer Through Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation

<ns3:p>Background Colorectal cancer (CRC) ranks among the leading causes of cancer-related morbidity and mortality worldwide, yet effective preventive strategies targeting its complex molecular basis remain limited. Vitamin D3 has demonstrated pleiotropic anticancer properties in CRC; however, the precise systems-level mechanisms underlying its chemopreventive roles remain incompletely understood. Methods CRC-associated target genes were retrieved from DisGeNET and GeneCards, while vitamin D3 targets were predicted via SwissTargetPrediction and the SEA platform. Overlapping targets were identified using InteractiVenn and subjected to PPI network construction via STRING (v12.0) and visualized in Cytoscape. Hub genes were identified using the CytoHubba plugin, followed by GO and KEGG enrichment analyses using DAVID 2022. Molecular docking was performed using MOE 2022.02, and molecular dynamics simulations were conducted using YASARA Dynamics over 50 ns under physiological conditions, with structural stability assessed via RMSD analysis. Results A total of 110 overlapping targets were identified, with PPI analysis revealing ten hub genes — CYP19A1, AR, ESR1, MELK, CDK4, AURKA, CYP17A1, TOP2A, CDC45, and SRD5A1 — enriched in signal transduction, steroid metabolic processes, and the ErbB–MAPK signaling pathway. Molecular docking confirmed favorable binding affinities (−5.72 to −8.74 kcal/mol), with CYP19A1, SRD5A1, and CDC45 showing the strongest interactions. Molecular dynamics simulations confirmed stable binding conformations, particularly for AR and CDC45 (RMSD ~1.2–1.5 Å). Conclusion VD3 exerts potential chemopreventive effects against CRC through a multi-target mechanism involving cell cycle regulation, proliferative signaling, and steroid hormone metabolism, suggesting it modulates colorectal carcinogenesis by coordinating multiple signaling pathways.</ns3:p>