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Updated: Aug 21, 2026
Revealing the Ferroptotic Phenotype of Medulloblastoma
Published on: March 15, 2024
MLN4924 enhances RSL3-induced ferroptosis sensitivity in glioblastoma via inhibiting the STAT3/GPX4 axis
Zhou Jing1,2,3, Fangyuan Wang1,2, Hao Li1,2,3
1Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China.
Abstract:
Glioblastoma (GBM) is one of the most aggressive and treatment-resistant tumors of the central nervous system, demanding innovative therapeutic strategies. Ferroptosis, an iron-driven lipid peroxidation-dependent cell death, has emerged as a potential means to overcome resistance, with glutathione peroxidase 4 (GPX4) as its key suppressor. MLN4924 (pevonedistat), a first-in-class inhibitor of neddylation currently in clinical trials, has shown strong antitumor activity across multiple malignancies. However, its role in ferroptosis regulation and the underlying molecular mechanisms remain poorly defined. Here, we show that MLN4924 induces ferroptosis, with GPX4 emerging as a central regulatory node. GPX4 expression is elevated in gliomas compared to normal brains, and its higher levels correlate with increased grades and worse patient prognosis. MLN4924 downregulates GPX4 mRNA by suppressing STAT3 signaling, whereas RSL3 directly inhibits GPX4 enzymatic activity. The combination of MLN4924 and RSL3 synergistically potentiates ferroptosis and, in vivo, suppresses subcutaneous tumor growth with a considerable biosafety. Collectively, these findings identify GPX4 as the principal mediator of MLN4924-induced ferroptosis and establish that dual targeting of GPX4 transcription and activity represents a promising therapeutic strategy for GBM.
Insights
MLN4924 induces cancer cell death via ferroptosis by targeting glutathione peroxidase 4 (GPX4). Combining MLN4924 with RSL3 shows promise for glioblastoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Glioblastoma (GBM) is a highly aggressive brain tumor with limited treatment options.
- Ferroptosis, an iron-dependent cell death, is a potential strategy to overcome treatment resistance.
- Glutathione peroxidase 4 (GPX4) is a key suppressor of ferroptosis.
Purpose of the Study:
- To investigate the role of MLN4924 (pevonedistat) in ferroptosis regulation.
- To elucidate the molecular mechanisms underlying MLN4924-induced ferroptosis.
- To evaluate the therapeutic potential of targeting GPX4 in glioblastoma.
Main Methods:
- Assessing MLN4924's effect on ferroptosis induction and GPX4 expression.
- Analyzing GPX4 expression levels in glioma tissues.
- Investigating the impact of MLN4924 on STAT3 signaling.
- Evaluating the synergistic effect of MLN4924 and RSL3 in vitro and in vivo.
Main Results:
- MLN4924 induces ferroptosis by downregulating GPX4 mRNA through STAT3 inhibition.
- Elevated GPX4 expression in gliomas correlates with higher tumor grade and poorer prognosis.
- Combined treatment with MLN4924 and RSL3 synergistically enhances ferroptosis and suppresses tumor growth in vivo with good safety.
- GPX4 is identified as a central mediator of MLN4924-induced ferroptosis.
Conclusions:
- MLN4924 is a potent inducer of ferroptosis in glioblastoma.
- Targeting GPX4 transcription and activity represents a promising therapeutic strategy for GBM.
- Dual targeting of GPX4 offers a novel approach for glioblastoma treatment.