Integrated Network and Transcriptomic Analyses Identify a Candidate Ethanol-ADAM17 Molecular Axis Associated with...

Glioblastoma (GBM) is the most aggressive brain tumor, with a median survival of approximately 15 months despite multimodal therapy. Although ethanol (EtOH) exposure has been associated with tumor-promoting inflammatory and signaling alterations, the molecular mediators linking EtOH to GBM progression remain poorly defined. We used Ingenuity Pathway Analysis (IPA) to construct independent EtOH- and ADAM17-associated molecular networks and identify shared regulatory effectors. Comparison of 921 EtOH-associated and 594 ADAM17-associated molecules identified 97 overlapping molecules, of which 25 were retained as high-confidence shared effectors. IPA disease-association analysis identified GBM as the strongest disease association in both the ADAM17 and integrated EtOH-ADAM17 networks. Computational network perturbation analyses indicated that simulated removal of ADAM17 eliminated the GBM disease association, whereas retention of ADAM17 as the central hub produced only a partial association, supporting its role as a key regulator within the predicted network. Analysis of TCGA-GBM transcriptomic data identified significant upregulation of ADAM17, CAV1, FLNA, and CASP8. Canonical pathway analysis further identified enrichment of ADAM17-associated signaling pathways, including sheddase, EGFR, ERBB4, neuregulin, JAK/IL-6, and matrix metalloproteinase signaling. Collectively, these findings support a candidate EtOH-ADAM17 molecular axis associated with GBM progression, providing a rationale for experimental evaluation of ADAM17 as a therapeutic target.