Related Experiment Video

Updated: Jun 28, 2026

Revealing the Ferroptotic Phenotype of Medulloblastoma
04:01

Revealing the Ferroptotic Phenotype of Medulloblastoma

Published on: March 15, 2024

Ferroptosis-induced oxidative stress in therapy-resistant glioblastoma

Sofia Remedia1,2,3, Cristina Martelli4, Marcella Bonanomi1

  • 1Institute of Bioimaging and Biological Complex Systems (IBSBC), National Research Council (CNR), Segrate (MI), Italy.

Cell Death Discovery
|June 26, 2026
PubMed

Insights

Ferroptosis, a cell death pathway, offers a new strategy against temozolomide-resistant glioma. Inducing ferroptosis overcomes resistance by targeting oxidative stress and reducing tumor growth.

Area of Science:

  • Oncology
  • Cell Death Mechanisms
  • Neuro-oncology

Background:

  • Temozolomide (TMZ) resistance is a significant challenge in treating gliomas.
  • Ferroptosis, a distinct form of regulated cell death, presents a potential therapeutic avenue.
  • Understanding ferroptosis sensitivity in TMZ-resistant glioma is crucial for developing novel treatments.

Purpose of the Study:

  • To investigate the molecular mechanisms governing ferroptosis sensitivity in temozolomide-resistant glioma cells.
  • To explore the roles of hypoxia-inducible factor 1-alpha (HIF-1α) and oxidative stress in this context.
  • To evaluate the therapeutic potential of ferroptosis induction in preclinical glioma models.

Main Methods:

  • Utilized one TMZ-sensitive and three TMZ-resistant human glioma cell lines.
  • Administered ferroptosis inducers (Erastin, FIN56, RSL3) and assessed cell viability, reactive oxygen species (ROS), and lipid peroxidation.
  • Investigated ferroptosis-related gene and protein expression, including GPX4, xCT, FSP1, and ATF4.
  • Employed MitoTEMPO and deferoxamine (DFX) to probe mitochondrial ROS and iron dependency.
  • Conducted integrated metabolomic-proteomic analyses and utilized an orthotopic U118-Luc xenograft model.

Main Results:

  • Ferroptosis inducers effectively reduced viability and bypassed TMZ resistance in vitro, suppressing tumor growth in vivo.
  • TMZ-resistant cells exhibited elevated HIF-1α, increased glutathione (GSH)/NRF2 activity, and reduced lipid peroxidation.
  • Ferroptosis induction increased oxidative stress, downregulated key ferroptosis regulators (GPX4, xCT, FSP1, ATF4), and implicated mitochondrial ROS.
  • MitoTEMPO treatment rescued cells, confirming the role of mitochondrial ROS.
  • Ferroptosis induction decreased HIF-1α expression and nuclear localization, along with HIF-1α/VEGF/SOX2/NRF2 signaling in tumor tissues.

Conclusions:

  • Ferroptosis induction represents a promising strategy to overcome temozolomide resistance in glioma.
  • HIF-1α and oxidative stress are key determinants of ferroptosis sensitivity in TMZ-resistant gliomas.
  • Targeting ferroptosis, particularly involving mitochondrial ROS, offers a viable therapeutic approach for aggressive glioma treatment.

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