NRF2 connects Src tyrosine kinase to ferroptosis resistance in glioblastoma

Glioblastoma is a severe brain tumor characterized by an extremely poor survival rate of patients. Glioblastoma cancer cells escape to standard therapeutic protocols consisting of a combination of ionizing radiation and temozolomide alkylating drugs that trigger DNA damage by rewiring of signaling pathways. In recent years, the up-regulation of factors that counteract ferroptosis has been highlighted as a major driver of cancer resistance to ionizing radiation, although the molecular connection between the activation of oncogenic signaling and the modulation of ferroptosis has not been clarified yet. Here, we provide the first evidence for a molecular connection between the constitutive activation of tyrosine kinases and resistance to ferroptosis. Src tyrosine kinase, a central hub on which deregulated receptor tyrosine kinase signaling converge in cancer, leads to the stabilization and activation of NRF2 pathway, thus promoting resistance to ionizing radiation-induced ferroptosis. These data suggest that the up-regulation of the Src–NRF2 axis may represent a vulnerability for combined strategies that, by targeting ferroptosis resistance, enhance radiation sensitivity in glioblastoma.