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Peer-reviewedCC BYOncogenesis

Tipping the balance: NRF2’s dual role in ferroptotic fate

  • Izadora de Souza1,2
  • Ana Beatriz da Silva Teixeira1
  • Ancély Ferreira dos Santos2
  • José Pedro Friedmann Angeli3,4
  • Clarissa Ribeiro Reily Rocha5
5 affiliations
  1. 1Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
  2. 2Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany
  3. 3Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany. [email protected]
  4. 4Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany. [email protected]
  5. 5Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil. [email protected]
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Abstract

The NRF2 pathway has emerged as a central regulator of cellular redox homeostasis, coordinating the expression of a broad array of genes that protect cells from oxidative and electrophilic stress. In the context of cancer, NRF2 has been recognized as a key driver of chemoresistance, as its sustained activation enhances antioxidant defenses, detoxification pathways, and metabolic adaptation, thereby promoting tumor cell survival under therapeutic stress. Beyond its canonical role in redox regulation, NRF2 also orchestrates the expression of multiple genes involved in ferroptosis, a non-apoptotic, iron-dependent form of cell death that has recently gained attention as a promising strategy to overcome drug resistance. Mechanistically, NRF2 modulates ferroptosis through several interconnected pathways, including the regulation of glutathione biosynthesis, lipid metabolism, and iron homeostasis, yet its impact is highly context-dependent and can vary according to cell type and metabolic state. In this review, we provide an overview of the interplay between NRF2 and ferroptosis, tracing the historical development of this network and highlighting the pivotal roles of specific NRF2 targets in controlling ferroptotic susceptibility. Finally, we discuss how targeted modulation of NRF2 may influence ferroptosis, offering a potential avenue for the design of innovative therapies aimed at selectively eradicating resistant tumors.

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Cite

BibTeXRIS
BibTeX
@article{souza2026tipping,
  title = {{Tipping the balance: NRF2’s dual role in ferroptotic fate}},
  author = {Izadora de Souza and Ana Beatriz da Silva Teixeira and Ancély Ferreira dos Santos and José Pedro Friedmann Angeli and Clarissa Ribeiro Reily Rocha},
  journal = {Oncogenesis},
  year = {2026},
  month = may,
  doi = {10.1038/s41389-026-00630-4},
  url = {https://doi.org/10.1038/s41389-026-00630-4},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Tipping the balance: NRF2’s dual role in ferroptotic fate
AU  - Izadora de Souza
AU  - Ana Beatriz da Silva Teixeira
AU  - Ancély Ferreira dos Santos
AU  - José Pedro Friedmann Angeli
AU  - Clarissa Ribeiro Reily Rocha
PY  - 2026
DA  - 2026/05/30
JO  - Oncogenesis
DO  - 10.1038/s41389-026-00630-4
UR  - https://doi.org/10.1038/s41389-026-00630-4
AB  - The NRF2 pathway has emerged as a central regulator of cellular redox homeostasis, coordinating the expression of a broad array of genes that protect cells from oxidative and electrophilic stress. In the context of cancer, NRF2 has been recognized as a key driver of chemoresistance, as its sustained activation enhances antioxidant defenses, detoxification pathways, and metabolic adaptation, thereby promoting tumor cell survival under therapeutic stress. Beyond its canonical role in redox regulation, NRF2 also orchestrates the expression of multiple genes involved in ferroptosis, a non-apoptotic, iron-dependent form of cell death that has recently gained attention as a promising strategy to overcome drug resistance. Mechanistically, NRF2 modulates ferroptosis through several interconnected pathways, including the regulation of glutathione biosynthesis, lipid metabolism, and iron homeostasis, yet its impact is highly context-dependent and can vary according to cell type and metabolic state. In this review, we provide an overview of the interplay between NRF2 and ferroptosis, tracing the historical development of this network and highlighting the pivotal roles of specific NRF2 targets in controlling ferroptotic susceptibility. Finally, we discuss how targeted modulation of NRF2 may influence ferroptosis, offering a potential avenue for the design of innovative therapies aimed at selectively eradicating resistant tumors.
SN  - 2157-9024
ER  -