NRF2 activation is required for chemotherapy resistance acquisition in medulloblastoma via metabolic and redox adaptation.
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This study explores the pivotal role of NRF2 signaling in conferring resistance to chemotherapy and ferroptosis in medulloblastoma (MB), a highly malignant pediatric brain tumor. Using newly developed in vitro models of MB cells, resistant to standard chemotherapeutics (vincistine, etoposide, cisplatin, and cyclophosphamide), we observed that chemotolerant cells exhibit an enhanced antioxidant response. Specifically, we found higher levels of glutathione, compared to sensitive cells, and increased thioredoxin reductase activity, both key components in maintaining redox homeostasis. Furthermore, we identified a metabolic shift in resistant cells, marked by increased flux through the pentose phosphate pathway (PPP), which boosts NADPH production and supports the antioxidant defense mechanisms. This adaptive antioxidant response is largely mediated by hyperactivation of the NRF2 transcription factor and the consequent upregulation of a set of antioxidant genes, thus effectively reducing intracellular reactive oxygen species (ROS) levels and enhancing cells' ability to tolerate oxidative stress. Intriguingly, our results suggest that NRF2 activation not only supports the acquisition of chemotherapy resistance but also confers protection against ferroptosis induction. Indeed, resistant cells upregulate iron sequestration proteins and ferroptosis-suppressing genes, directly controlled by NRF2, thereby reducing vulnerability to lipid peroxidation-induced cell death. Inhibition of NRF2 in resistant cells increased their sensitivity to both chemotherapy and ferroptosis inducers and, more interestingly, its knockdown prevented sensitive cells from acquiring resistance. Overall, our study underscores the crucial role of NRF2-controlled redox homeostasis in mediating resistance mechanisms in MB, highlighting the therapeutic potential of targeting this pathway. Targeting NRF2 signaling may provide a novel approach to overcome therapy resistance and improve treatment outcomes for patients with this challenging cancer.