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Updated: Dec 27, 2025

Extraction of Aqueous Metabolites from Cultured Adherent Cells for Metabolomic Analysis by Capillary Electrophoresis-Mass Spectrometry
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Extraction of Aqueous Metabolites from Cultured Adherent Cells for Metabolomic Analysis by Capillary Electrophoresis-Mass Spectrometry

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Metabolic features of cancer cells in NRF2 addiction status

Keito Okazaki1, Thales Papagiannakopoulos2, Hozumi Motohashi3

  • 1Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.

Biophysical Reviews
|March 1, 2020
PubMed

Insights

The KEAP1-NRF2 system regulates cellular defense against stress. In cancers, this system

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Oncology

Background:

  • The Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) pathway is crucial for cellular defense against oxidative and electrophilic stress.
  • KEAP1 normally inhibits NRF2, a transcription factor that activates genes involved in redox reactions.
  • Dysregulation of the KEAP1-NRF2 pathway leads to persistent NRF2 activation, a state known as NRF2 addiction in cancer cells.

Purpose of the Study:

  • To investigate the metabolic consequences of NRF2 addiction in cancer cells.
  • To elucidate how persistent NRF2 activation drives malignant progression and therapeutic resistance.
  • To identify novel therapeutic strategies targeting NRF2-addicted cancers based on their metabolic vulnerabilities.

Main Methods:

  • Analysis of gene expression patterns related to NRF2 targets.
  • Metabolic flux analysis in cancer cells with varying NRF2 activity.
  • Investigation of amino acid and glutathione metabolism.
  • Assessment of TCA cycle anaplerosis and mitochondrial respiration.

Main Results:

  • NRF2 addiction promotes metabolic reprogramming, including enhanced cystine uptake and glutathione synthesis.
  • This leads to increased glutamate consumption, limiting TCA cycle anaplerosis and mitochondrial respiration.
  • Cancer cells become dependent on exogenous non-essential amino acids.
  • Altered sulfur metabolism supports antioxidant capacity at the expense of central carbon metabolism.

Conclusions:

  • NRF2 addiction creates specific metabolic dependencies in cancer cells.
  • Targeting these metabolic vulnerabilities offers a promising therapeutic strategy for NRF2-addicted cancers.
  • Understanding the metabolic rewiring driven by NRF2 is key to developing effective cancer treatments.
Keywords:
CysteineGlutamateGlutathione synthesisKEAP1/NRF2Metabolic liabilitiesNon-essential amino acidsSulfur metabolism

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