Ferroptosis as a therapeutic target in glioblastoma: Mechanisms and emerging strategies

Abstract

Glioblastoma multiforme (GBM) is the most prevalent malignant brain tumor. Treating this type of cancer is challenging due to its high heterogeneity, rapid cell growth, and highly malignant nature, which results in a poor prognosis. A key feature of GBM's malignancy is that it resists drug treatments and evades cell death mechanisms. Ferroptosis is a promising therapeutic avenue for combating drug-resistant cancers because it is a recently discovered mechanism of programmed cell death that oxidizes membrane lipids and is triggered by an accumulation of reactive oxygen species. Recent findings suggest that ferroptosis is an innovative path for improving human GBM therapy. More exploration of the regulatory pathways and interactions of ferroptosis is essential to developing effective therapeutic strategies for this aggressive type of cancer. Inducing ferroptosis or integrating it with current treatments may present an opportunity to improve outcomes in GBM patients. This review investigates the role of ferroptosis in GBM and identifies its important molecular mediators. It also explores promising therapeutic strategies that target ferroptosis as a novel approach for GBM treatment.

Keywords: MT: Oligonucleotides: Therapies and Applications; ferroptosis; ferroptosis mediator; glioblastoma multiforme; glutathione depletion; iron metabolism; lipid peroxidation; targeting treatment.

Graphical abstract

Figure 1

A schematic of comparison of ferroptosis and the apoptosis pathway Apoptosis (left) is mediated by both extrinsic and intrinsic pathways. The extrinsic pathway is initiated by death receptors (TNFR1, FAS, DRS) binding their ligands, leading to the formation of the DISC and activation of caspase-8, which cleaves Bid into tBid, linking to the intrinsic pathway. The intrinsic pathway involves mitochondrial outer membrane permeabilization, primarily regulated by BCL-2 family proteins (BAX, BAK), resulting in cytochrome c release, apoptosome formation with APAF1, and activation of downstream caspases (caspase-9, -3, -7). Ferroptosis (right), in contrast, is a regulated cell death mechanism driven by iron-dependent lipid peroxidation. It is initiated by iron uptake through TF and TfR1, followed by Fe³⁺ reduction via STEAPs and participation in the Fenton reaction. PUFAs are incorporated into phospholipids (PE-PUFA) by ACSL4 and LPCAT3, leading to lipid peroxidation mediated by ALOXs. System xCT (SLC7A11/SLC3A2) imports cystine in exchange for glutamate (Glu), contributing to GSH synthesis. GSH acts as a cofactor for GPX4, which detoxifies lipid peroxides, preventing ferroptosis. Failure of GPX4 activity leads to uncontrolled lipid peroxidation and ferroptotic cell death. DISC, death-inducing signaling complex; DRS, death receptor FAS, fas receptor; Glu, glutamate; NAC, N-acetylcysteine; PUFAs, polyunsaturated fatty acids; TF, transferrin; TfR1, transferrin receptor; TNFR1, tumor necrosis factor receptor 1.

Figure 2

A schematic of three main ferroptosis pathways The key molecular mechanisms leading to ferroptosis through three interconnected pathways: (A) Iron metabolism pathway: Ferroptosis is driven by iron accumulation. Transferrin-bound Fe³⁺ is imported via TfR1 and reduced to Fe²⁺ by STEAP3, then transported into the cytosol by DMT1. Iron is either stored in ferritin, a complex containing FTH1, or released via ferritinophagy mediated by NCOA4. FTH1 oxidizes and stores Fe²⁺ in a non-toxic Fe³⁺ form, thereby limiting iron-driven ROS production. However, ferritin degradation increases cytosolic Fe²⁺, promoting the Fenton reaction and lipid ROS formation, thus sensitizing cells to ferroptosis. (B) Lipid peroxidation: PUFAs are esterified into membrane phospholipids (PL-PUFA-PE) by ACSL4 and LPCAT3. These are then peroxidized by LOXs or ROS, forming lipid LOOH. FSP1 contributes to ferroptosis resistance by reducing CoQ10 to CoQ10H₂ using NAD(P)H, countering lipid ROS. (C) Glutathione depletion pathway: Cystine is imported via system xCT (SLC3A2/SLC7A11) and converted to cysteine, which is used to synthesize GSH via GCL and GSS. GSH is a cofactor for GPX4, which reduces lipid peroxides to non-toxic lipid alcohols. When GSH is depleted or GPX4 is inhibited, lipid ROS accumulate, triggering ferroptosis. FTH1, ferritin heavy chain 1; LOXs, lipoxygenases; PUFAs, polyunsaturated fatty acids.

Figure 3

Summary of key mediators involved in GBM ferroptosis and their signaling pathways This schematic illustrates the complex regulatory network of ferroptosis in GBM. The xCT system (SLC7A11/SLC3A2) imports Cys in exchange for Glu. This enables cysteine synthesis, which fuels GSH production via enzymes GCL/GSS. GSH sustains redox balance and activates GPX4, which neutralizes lipid hydroperoxides (PUFA-PL-OOH) to prevent ferroptosis. The transsulfuration pathway (involving homocysteine and serine) also contributes to cysteine generation, independent of system xCT, and is upregulated under stress conditions (via ATF4). Iron metabolism proteins like NCOA4, Frataxin, and ALOX15 promote ROS generation via Fenton reactions and lipid peroxidation. Lipid metabolism enzymes ACSL4 and LPCAT3 convert PUFAs into phospholipid forms (PUFA-PL), which undergo peroxidation, leading to toxic lipid peroxide (PUFA-PL-OOH) buildup, a key hallmark of ferroptosis. Nrf2-Keap1 signaling protects against ferroptosis by promoting antioxidants like GPX4 and GSH. In contrast, SOCS1, TEAD/YAP/TAZ, and tumor suppressors (p53, BECN1) enhance ferroptosis. Deubiquitinases regulate this process: USP7 stabilizes p53, OTUB1 modulates SLC7A11, and BAP1 represses SLC7A11 via histone deubiquitination. CMTM5 and nuclear signals also influence ferroptosis sensitivity in GBM. Cys2, cystine; Cys, cysteine; Glu, glutamate.