Decoding ferroptosis and apoptosis crosstalk in glioblastoma: molecular mechanisms, microenvironmental regulation, and therapeutic advances.

Glioblastoma (GBM) is the most aggressive and lethal form of primary brain neoplasia, which is characterised by significant resistance to conventional therapeutic modalities and a very particular immunosuppressive environment. Programmed cell death mechanisms and the role of ferroptosis and apoptosis in particular have become promising therapeutic targets in the context of GBM. This review critically analyses the molecular basis of ferroptosis and apoptosis, focusing on the points of intersection and the regulation of both pathways, including p53 signalling and reactive oxygen species and mitochondrial pathways. We outline the mechanisms used by GBM cells to hijack these death pathways in favour of a survival response, and how the balance between ferroptosis and apoptosis might be manipulated to design more effective therapeutics. Moreover, the role of tumor microenvironmental hypoxia, immune cell infiltration and metabolic constraints on cellular susceptibility to death is discussed in depth. A thorough survey of small molecule agents that can induce ferroptosis or apoptosis is presented, and a special focus is given to dual acting compounds that display synergistic mechanisms. Existing preclinical data is reviewed and the potential advantages of combinatorial therapeutic approaches including delivery challenges like blood–brain barrier penetration are scrutinised. Integrating evolving insights in ferroptosis-apoptosis crosstalk and microenvironmental modulation for new avenues of rational drug design and translation research. Ultimately, the simultaneous targeting of ferroptosis and apoptosis is highly promising for overcoming resistance to therapy and improving the clinical outcome of patients suffering from GBM.