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Redox-dependent protein S-glutathionylation governs azacitidine sensitivity and resistance in AML

Dušan Nemes1, Michaela Myšáková1, Lubomír Minařík2

  • 1BIOCEV, First Faculty of Medicine, Charles University, Vestec, 25250, Czech Republic; Faculty of Science, Charles University, Prague, 128 00, Czech Republic.

Redox Biology
|December 13, 2025
PubMed

Insights

Drug resistance in acute myeloid leukemia (AML) involves altered redox metabolism. Restoring protein S-glutathionylation sensitizes resistant AML cells to azacitidine therapy.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Disrupted redox metabolism is characteristic of drug-resistant cancers, particularly acute myeloid leukemia (AML).
  • Understanding protein redox signaling in AML drug resistance is crucial for developing effective therapies.
  • Azacitidine (AZA) is a hypomethylating agent used in AML treatment, but resistance limits its efficacy.

Purpose of the Study:

  • To investigate the role of protein redox signaling in azacitidine (AZA) resistance in acute myeloid leukemia (AML).
  • To identify mechanisms underlying redox homeostasis disruption and restoration in AZA-resistant AML.
  • To explore therapeutic strategies for overcoming AZA resistance by targeting redox pathways.

Main Methods:

  • Comprehensive mass spectrometry-based redox and quantitative proteomic profiling.
  • Analysis of AML cell lines and patient samples sensitive or resistant to azacitidine (AZA).
  • Assessment of glyoxalase system and DNA damage response pathways.

Main Results:

  • Azacitidine (AZA) disrupts redox homeostasis, inactivating the glyoxalase system and DNA damage response, leading to cell death in sensitive AML.
  • AZA resistance is linked to a redox reset with elevated glutathione and reduced protein S-glutathionylation.
  • AZA failed to induce protein oxidation in key pathways in resistant AML cells and patient samples.
  • Pharmacological inhibition of glutathione synthesis restored protein S-glutathionylation and AZA sensitivity in resistant AML cells.

Conclusions:

  • AZA resistance in AML involves a failure to disrupt redox homeostasis, characterized by elevated glutathione levels.
  • Targeting glutathione synthesis can restore protein S-glutathionylation and overcome AZA resistance in AML.
  • These findings highlight redox signaling as a therapeutic vulnerability in AZA-resistant AML.
Keywords:
Acute myeloid leukemiaAzacitidineCysteine oxidationDNA damageDrug resistanceGlyoxalase systemHypomethylation therapyRedox proteomicsS-glutathionylation

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