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Updated: Jan 9, 2026

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Mitochondrial Metabolic Reprogramming along with NRF2/KEAP1-Mediated Antioxidant Mechanisms Drive Temozolomide

Manendra Singh Tomar1, Chirag Kulkarni2,3,4, Kaveri R Washimkar5,3,4

  • 1Center for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow-226003, Uttar Pradesh India.

Journal of Proteome Research
|December 5, 2025
PubMed

Insights

Glioblastoma cells develop resistance to temozolomide (TMZ) therapy by altering their metabolism. Enhanced mitochondrial activity and antioxidant defenses, driven by NRF2, contribute to this drug resistance.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • Molecular Biology

Background:

  • Temozolomide (TMZ) is a standard chemotherapy for glioblastoma multiforme (GBM).
  • Acquired resistance to TMZ significantly limits treatment efficacy in approximately half of GBM patients.
  • Understanding the mechanisms of TMZ resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the role of cellular bioenergetics and metabolism in acquired TMZ resistance in GBM.
  • To identify key metabolic alterations and molecular pathways contributing to TMZ resistance.

Main Methods:

  • Utilized untargeted metabolomics to analyze metabolic profiles of TMZ-resistant GBM cells.
  • Assessed mitochondrial function, including mass and membrane potential.
  • Quantified levels of key proteins and metabolites, including NRF2, KEAP1, glutathione, and catalase.

Main Results:

  • TMZ-resistant GBM cells exhibit significant metabolic rewiring, including alterations in glycolysis, TCA cycle, and amino acid metabolism.
  • Increased mitochondrial activity, mass, and membrane potential correlate with enhanced drug resistance.
  • Elevated glutamine levels support increased mitochondrial energy production.
  • Upregulation of the NRF2/KEAP1 pathway leads to increased antioxidant levels (glutathione, catalase), mitigating oxidative stress and contributing to resistance.

Conclusions:

  • Mitochondrial metabolic reprogramming and NRF2/KEAP1-mediated antioxidant defense are critical mechanisms in acquired TMZ resistance in GBM.
  • Targeting these metabolic and antioxidant pathways presents a potential novel strategy to overcome TMZ resistance in glioblastoma therapy.
Keywords:
drug resistanceglioblastoma multiformemitochondria metabolismoxidative stresstemozolomide

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