[Preliminary investigation into the mechanisms of thalidomide in inhibiting the malignant transformation of oral leukoplakia].

Abstract

Objectives: This study aims to integrate network pharmacology, machine learning, and survival analysis to preliminarily explore the molecular mechanisms underlying the inhibitory effects of thalidomide on the malignant transformation of oral leukoplakia (OLK).

Methods: First, multisource databases and an OLK transcriptomic cohort (GSE26549) were integrated to identify the intersecting feature genes between thalidomide and OLK with epithelial dysplasia, followed by pathway enrichment analysis. Subsequently, a protein-protein interaction (PPI) network was constructed, and ensemble machine learning algorithms were applied to screen for core biomarkers. Kaplan-Meier curves and multivariate Cox proportional hazard regression models were utilized to evaluate the clinical prognostic efficacy of these core biomarkers. Finally, molecular docking was employed to validate the physical binding potential between thalidomide and the core biomarkers of OLK.

Results: A total of 16 intersecting target genes between thalidomide and OLK with epithelial dysplasia were identified. These genes were primarily enriched in the signaling pathways of the cell cycle, phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt), and microRNAs in cancer. PPI network analysis combined with ensemble algorithms ultimately identified four core biomarkers: MET proto-oncogene, receptor tyrosine kinase (MET), Aurora kinase A (AURKA), DNA methyltransferase 1 (DNMT1), and poly(ADP-ribose) polymerase 1 (PARP1). Survival analysis revealed that high expression levels of MET (P=0.004) and AURKA (P=0.029) increased the risk of malignant transformation in OLK. Furthermore, MET exhibited crucial independent prognostic value in the multivariate Cox proportional hazard regression model (hazard ratio=2.58, P=0.051). Molecular docking demonstrated that thalidomide could stably bind to the MET receptor (binding energy=-38.178 kJ/mol).

Conclusions: Thalidomide may exert its inhibitory effects against the malignant progression of OLK by primarily targeting MET and synergistically ac-ting on key biomarkers, including AURKA, DNMT1, and PARP1, thereby suppressing downstream PI3K-Akt and cell cycle signaling pathways. This study not only provides robust computational biology evidence for the "drug repurpo-sing" of thalidomide but also highlights a promising pharmacological option for the clinical intervention of OLK's malignant transformation.