Exploiting Integrin-αVβ3 to Enhance Radiotherapy Efficacy in Medulloblastoma via Ferroptosis

Medulloblastoma, a malignant pediatric brain tumor, has a poor prognosis upon relapse, highlighting a critical clinical need. Our previous research linked medulloblastoma cell radioresistance to integrin-αvβ3 expression. β3-depleted (β3_KO) medulloblastoma cells exhibit lipid hydroxyperoxide accumulation after radiotherapy, indicating ferroptosis, a regulated cell death induced by ROS and inhibited by antioxidants such as cysteine, glutathione (GSH), and glutathione peroxidase 4 (GPx4). However, the link between αvβ3 expression, ferroptosis inhibition, and sensitivity to radiotherapy remains unclear. We showed that irradiated β3_KO medulloblastoma cells primarily die by ferroptosis, with β3-subunit expression correlating with radiotherapy sensitivity and anti-ferroptotic protein levels. Our findings suggest that integrin-αvβ3 signaling boosts oxidative stress resilience via mTORC1. Thus, targeting integrin-αvβ3 could enhance radiotherapy efficacy in medulloblastoma by inducing ferroptotic cell death.