Abstract
Purpose: Thymic epithelial tumors, although rare neoplasms, are the most common tumors of the anterior mediastinum. They are generally treated with surgery; however, they may also require chemotherapy. Melatonin, known for regulating circadian rhythms, has demonstrated anti-cancer properties However, its effects on thymic epithelial tumors have not yet been investigated.Materials and Methods: Melatonin and thymoma-related proteins (2170 genes) were screened from various databases. Then, protein-protein interaction network of the intersected genes (316 genes) was constructed using STRING database. Cytoscape was utilized to determine hub genes .Results: KEGG analysis revealed the associated pathways as PI3K-AKT, MAPK, HIF-1, and FOXO. Molecular docking and dy-namics simulations revealed high conformational stability between melatonin and hub genes, notably ESR1 (ER-alpha) and FOS. ESR1 exhibited the lowest MMPBSA binding enthalpy (-100.36 kJ/mol from 100-ns MD simulations), which is distinct from the initial docking scores. Although TP53 showed the lowest docking binding free energy (-11.49 kcal/mol), ESR1 demonstrated superior conformational stability and enthalpic favorability throughout the MD trajectory, suggesting a critical role in modulating estrogen receptor-mediated transcriptional activity. The high conformational stability in ESR1/melatonin complex could modulate the activity of estrogen receptor-α and probably inhibit cancer cell growth and progression through the regulation of PI3K/AKT and MAPK pathways. Additionally, melatonin interactions with p53, SMAD3, MYC, and STAT3 suggest a broader impact on tumor cell regulation and survival pathways. Conclusion: These findings provide novel insights into the molecular mechanisms underlying melatonin’s anti-cancer effects on thymoma and related cancer types, offering a potential avenue for targeted therapeutic interventions.