Ioning out glioblastoma: ferroptosis mechanisms and therapeutic frontiers

Abstract Glioblastoma (GBM) (IDH-wildtype), the most prevalent and malignant primary brain tumor in adults, continues to pose a major therapeutic challenge in neuro-oncology. Despite significant advancements in cancer diagnosis and treatment technologies, conventional therapies remain largely ineffective against this tumor, urgently necessitating breakthrough treatment strategies. This comprehensive review critically examines recent advances in targeting ferroptosis, an iron-dependent form of non-apoptotic cell death mediated through reactive oxygen species (ROS) accumulation and lipid membrane peroxidation, for therapeutic intervention in GBM. The key aspects analyzed encompass the unique molecular mechanisms that distinguish ferroptosis from apoptosis and necrosis, along with its regulatory networks in GBM. The analysis also explores the therapeutic potential of targeting critical ferroptosis pathways, including dysregulated iron metabolism, impaired antioxidant defenses, and abnormal lipid peroxidation. Additionally, it examines the synergistic effects and molecular basis of combining ferroptosis inducers with chemo-radiotherapy or immunotherapy. Finally, the study highlights innovative applications of nano-drug delivery technologies in overcoming blood-brain barrier (BBB) limitations and enhancing the precision of ferroptosis-targeted therapy. Notably, this review provides a comprehensive analysis of the interplay between ferroptosis regulation and the tumor immune microenvironment, highlighting a promising ‘ferroptosis-immunotherapy’ combination strategy with clinical translation potential for GBM treatment. While challenges persist regarding incomplete understanding of regulatory networks and nanocarrier biosafety issues, this review not only provides a theoretical framework for comprehending ferroptosis-mediated anti-GBM mechanisms but also outlines future research directions, including in-depth dissection of ferroptosis signaling hubs, development of intelligent nano-delivery systems, and establishment of preclinical safety evaluation protocols. These findings are expected to provide revolutionary therapeutic targets for achieving precision treatment of GBM.