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NRF2 activation in cancer and overview of NRF2 small molecule inhibitors

Hoang Hai Ngo1, Bo-Yeong Yu1, Jeong-Eun Lee1

  • 1College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University, 32 Dongguk-Ro, Goyang, 10326, Gyeonggi-Do, Korea.

Archives of Pharmacal Research
|August 15, 2025
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (NRF2) normally protects cells but drives cancer chemoresistance when mutated. This review explores NRF2 regulation, its role in chemoresistance, and therapeutic strategies targeting NRF2-addicted cancer cells.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor crucial for antioxidant and detoxification responses.
  • While NRF2 activation by phytochemicals is protective in normal cells, its aberrant activation in cancer promotes tumor growth and chemoresistance.
  • Mutations in the KEAP1/NRF2 pathway drive oncogenic NRF2 activity, creating a pro-tumorigenic microenvironment.

Purpose of the Study:

  • To elucidate the regulatory mechanisms governing NRF2.
  • To discuss the role of NRF2 activation in conferring chemoresistance to cancer cells.
  • To explore therapeutic strategies targeting cancer cells dependent on NRF2.

Main Methods:

  • Review of existing literature on NRF2 regulation and function in cancer.
  • Analysis of molecular mechanisms underlying NRF2-mediated chemoresistance.
  • Examination of therapeutic approaches, including small-molecule NRF2 inhibitors.

Main Results:

  • NRF2 regulates diverse cellular processes beyond redox homeostasis, including metabolism and proteostasis.
  • Aberrant NRF2 activation in cancer contributes to proliferation, survival, and resistance to chemotherapy.
  • Specific therapeutic strategies targeting NRF2-dependent cancer vulnerabilities are being developed.

Conclusions:

  • Understanding NRF2 regulation is key to deciphering its dual role in cancer.
  • Targeting NRF2 offers a promising avenue for overcoming cancer chemoresistance.
  • NRF2 small-molecule inhibitors represent a potential therapeutic strategy for NRF2-addicted cancers.
Keywords:
NRF2 small molecule inhibitorsNuclear factor erythroid 2-related factor 2 (NRF2)

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