Mitochondrial dysfunction and its impact on pyroptosis and ferroptosis cross talk in glioma cells

Glioblastomas (GBM), the most aggressive primary brain tumors, remain challenging to treat due to their rapid proliferation, invasiveness, and resistance to current therapies. Emerging evidence highlights pyroptosis and ferroptosis as critical regulators of tumor progression. This review elucidates the pivotal role of mitochondrial dysfunction in driving these programmed cell death pathways in GBM. Specifically, mitochondrial abnormalities induce overproduction of reactive oxygen species (ROS) and disrupt iron homeostasis, thereby triggering pyroptosis through inflammasome activation and ferroptosis via lipid peroxidation accumulation. Impaired mitochondrial dynamics, such as membrane potential collapse, pro-inflammatory cytokine release, and defective mitophagy, synergistically determine tumor cell fates. We propose novel therapeutic strategies targeting mitochondrial ROS-scavenging systems, iron-sulfur cluster biosynthesis, and mitophagy modulation to overcome resistance to treatment of GBM. These investigations not only advance the understanding of the pathobiology of GBM but also underscore mitochondria as multifaceted therapeutic hubs and offer translational potential for other diseases linked to mitochondrial dysregulation. By integrating cutting-edge research data, this review establishes a foundation for developing precision therapies centered on pyroptosis and ferroptosis modulation, bridging mechanistic discoveries with clinical innovation in neuro-oncology.