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Nuclear factor erythroid 2-related factor 2 (Nrf2) inhibition revisited: advances and unmet challenges

Mengchen Lu1, Ziyu Yang1, Yabing Xin1

  • 1Jiang Su Key Laboratory of Antibody-Targeted Drug Research, School of Pharmacy, Suzhou Medical College, Soochow University, Suzhou 215006, China.

Journal of Advanced Research
|May 18, 2026
PubMed
Abstract

Insights

Nuclear factor erythroid 2-related factor 2 (NRF2) has dual roles in cell protection and cancer promotion. Targeting its tumor-promoting functions offers a path to effective cancer therapies.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of cellular stability, impacting protein integrity, metabolism, immunity, and iron homeostasis.
  • NRF2 exhibits dual functions: cytoprotective ('Yang phase') under stress and tumor-promoting ('Yin phase') upon aberrant activation, particularly in cancer.
  • NRF2's complex roles in diseases like cancer, metabolic disorders, and neurodegeneration necessitate a comprehensive understanding for therapeutic development.

Purpose of the Study:

  • To systematically review the multifaceted biological functions of NRF2, emphasizing its context-dependent roles in cancer progression.
  • To integrate current knowledge on NRF2's dualistic functions in cellular homeostasis and tumor development.
  • To explore NRF2 inhibition strategies, investigational agents, and clinical translation challenges.

Main Methods:

  • Systematic literature review and synthesis of existing research on NRF2.
  • Analysis of NRF2's regulatory network and its implications in various diseases.
  • Evaluation of preclinical NRF2 inhibitors and their mechanisms of action.

Main Results:

  • NRF2's dualism presents a significant challenge for therapeutic targeting, balancing its essential cytoprotective roles with its oncogenic potential.
  • Preclinical NRF2 inhibitors show promise but face limitations in specificity and efficacy.
  • Selective inhibition of the tumor-promoting 'Yin phase' of NRF2 is identified as a key strategy for cancer therapy.

Conclusions:

  • Resolving the paradox of NRF2's dual roles through precision strategies is crucial for unlocking its therapeutic potential in cancer.
  • Bridging NRF2 biology with translational oncology and precision medicine frameworks can advance NRF2-targeted therapies.
  • Further research and development are needed to overcome challenges in translating NRF2 inhibitors into clinical practice.
Keywords:
CancerKEAP1-NRF2 signalingNRF2 inhibitorOxidative stressTargeted protein degradation

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