Investigating the prognostics and theranostic cell cycle-related genes of Hinokinin in high-grade glioma: an integrated network pharmacology, bioinformatics, and molecular docking approach.

backgroundGlioblastoma (GBM) is the most malignant and prevalent primary brain tumor in adults, accounting for up to 60% of all adult brain tumor, classified as WHO grade 4. Uncontrolled cell-cycle progression is one of the hallmarks of GBM. The patient prognosis is still poor after multimodal treatment, underscoring the need for new therapeutic strategies. Derived from Piper cubeba, hinokinin is a bioactive dibenzylbutyrolactone lignan that has demonstrated interesting anticancer effects. However, little is known about its molecular processes in GBM.

methodsTo understand the therapeutic potential of Hinokinin in GBM, we used an integrated network pharmacology, transcriptomic and molecular docking method. GBM-related genes and differentially expressed genes (DEGs) were found in the GeneCards and GEPIA2 databases. Hinokinin-associated targets were predicted using SwissTargetPrediction. Protein-protein interaction (PPI) networks, Gene Ontology (GO), and KEGG pathway enrichment analyses were used to further evaluate the core targets that were identified by intersecting these datasets. Expression profiling, survival analysis, immune infiltration analysis, genetic alteration analysis, and scRNA-sequencing datasets were used to determine clinical significance. Hinokinin's binding affinity and drug-likeness were evaluated using molecular docking and ADMET analyses.

resultsHinokinin's targets in GBM were found to be 36 overlapping genes with enrichment in cell-cycle regulation, kinase activity, and carcinogenic pathways. CDK2, PLK1, CHEK1, AURKA, and AURKB were identified as important hub genes by PPI network analysis. These genes were related in tumors with p53/Rb alterations, markedly elevated in GBM tissues, linked to poor overall survival (OS), and mostly expressed at the single-cell level in malignant cell types. Strong negative relationships between hub gene expression and several immune cell types were found by immune infiltration analysis. Frequent transcriptional dysregulation of these kinases was shown by genetic alteration analysis, and this was associated with a poor prognosis. Hinokinin interacts to all five hub proteins with strong binding energies. Drug-likeness and blood brain barrier (BBB) permeability, were validated by ADMET.

conclusionOur findings highlight that Hinokinin may have antitumor effects in GBM targeting key cell-cycle and mitotic kinases involved in tumor growth and poor prognosis. These results provide a strong mechanistic rationale for Hinokinin as a promising multitarget therapeutic for GBM.