Emerging role of ferroptosis in glioblastoma: Therapeutic opportunities and challenges

Abstract

Glioblastoma (GBM) is the most common malignant craniocerebral tumor. The treatment of this cancer is difficult due to its high heterogeneity and immunosuppressive microenvironment. Ferroptosis is a newly found non-apoptotic regulatory cell death process that plays a vital role in a variety of brain diseases, including cerebral hemorrhage, neurodegenerative diseases, and primary or metastatic brain tumors. Recent studies have shown that targeting ferroptosis can be an effective strategy to overcome resistance to tumor therapy and immune escape mechanisms. This suggests that combining ferroptosis-based therapies with other treatments may be an effective strategy to improve the treatment of GBM. Here, we critically reviewed existing studies on the effect of ferroptosis on GBM therapies such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy. In particular, this review discussed the potential of ferroptosis inducers to reverse drug resistance and enhance the sensitivity of conventional cancer therapy in combination with ferroptosis. Finally, we highlighted the therapeutic opportunities and challenges facing the clinical application of ferroptosis-based therapies in GBM. The data generated here provide new insights and directions for future research on the significance of ferroptosis-based therapies in GBM.

An atlas of causal and mechanistic drivers of interpatient heterogeneity in glioma

“…In addition to showcasing the sensitivity of gbmMINER in delineating disease-driving mechanisms in a small subgroup of patients within a larger cohort, this finding also underscores generalizability of the mechanisms by which IDH1 acts through a combinatorial network to activate ferroptosis. While there is evidence in literature that both IDH1 and TP53 regulate ferroptosis, the primary mechanism was unknown 72 . In fact, a recent study discovered that although the acetylation-defective mutant TP53 3KR lost its ability to induce cell senescence, apoptosis, and cell-cycle arrest, it was still able to inhibit tumorigenesis by inducing ferroptosis 73 .…”

Diethyldithiocarbamate-ferrous oxide nanoparticles inhibit human and mouse glioblastoma stemness: aldehyde dehydrogenase 1A1 suppression and ferroptosis induction

“…The potent anti-stemness influence of DE-FeONPs is attributed to inhibiting ALDH1A1 and inducing lipid peroxidation-dependent ferroptosis ( Abu-Serie, 2024 ). Since, the balance between reactive radical species and antioxidants is primarily responsible for therapeutic resistance in GBM ( Zhuo et al, 2022 ), inducing ferroptosis could be one of the most promising treatments ( Luo et al, 2022 ; Xue et al, 2024 ). Notably, GSCs have a higher capacity than normal brain cells for iron uptake by upregulating the expression of its receptor ( Park et al, 2019 ).…”

“…These novel cell death pathways including the accumulated copper-mediated cuproptosis and iron-mediated ferroptosis, lead to mitochondrial dysfunction and uncontrolled lipid peroxidation, respectively ( Tang et al, 2021 ; Abu-Serie, 2023 ; Abu-Serie and Abdelfattah, 2023 ). Ferroptosis inducers can thus improve sensitivity of GBM to chemotherapeutic drugs (e.g., TMZ), radiation, and immunotherapy as well as targeted therapy (e.g., epidermal growth factor receptor inhibitors) and inhibit metastasis ( Zhuo et al, 2022 ; Bo et al, 2024 ; Wang et al, 2024 ). Ferroptosis is exacerbated by the inhibition of the antioxidant glutathione system, including glutathione peroxidase (GPX)4 and its substrate glutathione (GSH) ( Koppula et al, 2021 ; Zhuo et al, 2022 ).…”

“…Ferroptosis inducers can thus improve sensitivity of GBM to chemotherapeutic drugs (e.g., TMZ), radiation, and immunotherapy as well as targeted therapy (e.g., epidermal growth factor receptor inhibitors) and inhibit metastasis ( Zhuo et al, 2022 ; Bo et al, 2024 ; Wang et al, 2024 ). Ferroptosis is exacerbated by the inhibition of the antioxidant glutathione system, including glutathione peroxidase (GPX)4 and its substrate glutathione (GSH) ( Koppula et al, 2021 ; Zhuo et al, 2022 ). This glutathione system suppression can be mediated by DE, which is a potent inhibitor of ALDH1A1 ( Abu-Serie and Abdelfattah, 2023 ).…”

Implantation of hydrogel-liposome nanoplatform inhibits glioblastoma relapse by inducing ferroptosis

“…Recent advances have identified that the hub genes of ferroptosis pathway, including cysteine-glutamate transporter (xCT) and glutathione peroxidase (GPX), play indispensable roles in the therapeutic resistance of tumors, especially for GBM [14] , [15] , [16] . Intervention of these key factors is proved to enhance the sensitivity of chemotherapy and radiotherapy, thus improving the prognosis of GBM [17] , [18] . Erastin (ERA) is the first small molecule inhibitor found to selectively and effectively mediate ferroptosis through xCT, voltage-dependent anion channel (VDAC) and p53.…”