AEG-1 on cancer drug resistance: From molecular insights to therapeutic challenges.

Astrocyte elevated gene-1 (AEG-1), also known as metadherin (MTDH), has emerged as a multifunctional oncogene implicated in cancer progression, metastasis, immune evasion, and notably, drug resistance across diverse malignancies. AEG-1 exerts its effects by modulating key signaling cascades, including PI3K/Akt, NF-κB, and Wnt/β-catenin, and by regulating genes associated with epithelial-mesenchymal transition, apoptosis suppression, cancer stemness, and multidrug resistance. Its interactions with molecular partners such as SND1, USP10, and nucleolin further amplify its oncogenic potential, especially in immune suppression and therapy resistance. This review provides a comprehensive overview of AEG-1-mediated drug resistance mechanisms across tumor types including breast, liver, lung, glioma, and gynecological cancers. Tumor-specific signaling contexts and immune microenvironmental interactions are examined to highlight how they shape AEG-1 function. Therapeutic challenges in targeting AEG-1-such as its non-enzymatic structure and intracellular localization-are critically discussed. We further explore emerging strategies to inhibit AEG-1, including RNA interference, long noncoding RNA modulation, partner interaction disruption, phytochemical inhibitors, and nanoparticle-based delivery systems. AEG-1 is also evaluated as a prognostic and predictive biomarker with translational relevance in precision oncology. Future studies should prioritize its integration into biomarker-guided clinical trials and the development of tumor-specific AEG-1-targeted therapies. This review underscores AEG-1 as a central mediator of drug resistance and a compelling target for next-generation cancer therapeutics.