Abstract: Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis, primarily due to its resistance to oxidative stress, which inhibits various forms of cell death, particularly ferroptosis. Recent studies have identified extracellular vesicles (EVs) as important mediators of intercellular communication, capable of transferring mitochondria between cells. This study explores whether EVs derived from adipose-derived mesenchymal stem cells (Ad-MSCs) under oxidative stress can transfer dysfunctional mitochondria to GBM cells, thereby overcoming their resistance to oxidative stress and specifically inducing ferroptosis. EVs were characterized and introduced to GBM cell lines, where ferroptosis was assessed by monitoring reactive oxygen species (ROS), lipid peroxidation, and mitochondrial membrane potential. Our findings demonstrate that EVs from stressed Ad-MSCs significantly increase ROS levels and lipid peroxidation in GBM cells, directly inducing ferroptosis. Downregulation of key ferroptosis markers, including GPX4, and the observation of mitochondrial dysfunction and iron dysregulation further confirm the induction of ferroptosis. These results provide new insights into overcoming GBM’s resistance to ferroptosis and suggest that Ad-MSC-derived EVs could be a promising strategy for targeted cancer therapy.
