AEG-1/MTDH: A central regulator of tumor progression, metabolic adaptation, and therapeutic resistance in gliomas.

Astrocyte-elevated gene-1 (AEG-1), also known as metadherin (MTDH), is a pleiotropic oncogene critically involved in the onset and development of glioblastoma (GBM), other malignant gliomas, and neuroblastoma. Its expression is upregulated under hypoxic conditions and during glucose deprivation, enabling tumor cells to survive severe metabolic stress while sustaining glycolysis. AEG-1 also has emerged as a reliable prognostic and diagnostic biomarker in gliomas, astrocytomas, oligodendrogliomas, and neuroblastomas. High AEG-1 expression correlates with advanced tumor grade, rapid disease progression, metastasis, and poor overall survival, independent of conventional clinical variables. Co-expression of AEG-1 with MDM2 further predicts higher recurrence and reduced survival, highlighting its value in patient stratification and clinical decision-making. Beyond its prognostic relevance, AEG-1 is a promising therapeutic target. Importantly, gene silencing studies demonstrate that AEG-1 knockdown reduces proliferation, promotes apoptosis, and enhances sensitivity to chemotherapeutic agents such as cisplatin, doxorubicin, and temozolomide. Mechanistically, inhibition of AEG-1 disrupts survival pathways including PI3K/Akt, impairs DNA repair, and attenuates immunosuppressive tumor microenvironments. Small-molecule inhibitors, such as DYT-40, synergistically target AEG-1 and NF-κB, reducing tumor growth and invasion in glioblastoma models. Moreover, AEG-1 suppression sensitizes cancer cells to radiotherapy by impairing homologous recombination repair and enhancing DNA damage-induced apoptosis. Collectively, these findings underscore AEG-1 as a central regulator of tumor progression, chemoresistance, and radioresistance, and support its potential as a target for combinatorial therapeutic strategies to improve outcomes in aggressive brain and pediatric tumors.