How to deal with frenemy NRF2 - Targeting NRF2 for chemoprevention and cancer therapy

Sep 24, 2026

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Induction of antioxidant proteins and phase 2 detoxifying enzymes that neutralize reactive electrophiles underpins protection against carcinogenesis. Normal cells use multifaceted pathways to tightly control NF-E2-related factor 2 (NRF2)-mediated gene expression after exposure to endogenous and exogenous oncogenic molecules. Transient NRF2 activation by its activators drives ARE-mediated cytoprotective proteins crucial for protection from toxic and oxidative damage, supporting efficacy in cancer chemoprevention. Yet NRF2’s cytoprotective function can also foster tumor progression, survival, and drug resistance via aberrant activation in many cancers. Pharmacological NRF2 inhibition is therefore a promising cancer therapy strategy. This review compiles NRF2 regulatory mechanisms and summarizes NRF2 modulators research progress, focusing on phytochemicals in chemoprevention and cancer therapy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Abstract

Discovery of NRF2

NRF2 structure and discovery

NRF2 target genes and regulation

Regulation of NRF2-ARE pathway

Ubiquitination and proteasomal degradation of NRF2

Review article scope and aims

| Volume 31 Issue 3 | Article 2 | | --- | --- | | How to deal with frenemy NRF2: Targeting NRF2 for chemoprevention and cancer therapy
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License. | | Recommended Citation Tang, Ya-Chu; Chuang, Yung-Jen; Chang, Hsin-Huei; Juang, Shin-Hun; Yen, Gow-Chin; Chang, Jang-Yang; and Kuo, Ching-Chuan (2023) "How to deal with frenemy NRF2: Targeting NRF2 for chemoprevention and cancer therapy,"Journal of Food and Drug Analysis: Vol. 31 : Iss. 3 , Article 2. Available at: [https://doi.org/10.38212/2224-6614.3463](https://doi.org/10.38212/2224-6614.3463) This Review Article is brought to you for free and open access by Journal of Food and Drug Analysis. It has been accepted for inclusion in Journal of Food and Drug Analysis by an authorized editor of Journal of Food and Drug Analysis. How to deal with frenemy NRF2: Targeting NRF2 for chemoprevention and cancer therapy Ya-Chu Tang a, Yung-Jen Chuang b,c, Hsin-Huei Chang a, Shin-Hun Juang d, Gow-Chin Yen e, Jang-Yang Chang a,f,g, Ching-Chuan Kuo a,h, * a Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan b School of Medicine, National Tsing Hua University, Hsinchu, Taiwan c Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan d School of Pharmacy, China Medical University, Taichung, Taiwan e Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan f Taipei Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan g TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan h Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan Abstract Induction of antioxidant proteins and phase 2 detoxifying enzymes that neutralize reactive electrophiles are important mechanisms for protection against carcinogenesis. Normal cells provide multifaceted pathways to tightly control NF-E2-related factor 2 (NRF2)-mediated gene expression in response to an assault by a range of endogenous and exogenous oncogenic molecules. Transient activation of NRF2 by its activators is able to induce ARE-mediated cytoprotective proteins which are essential for protection against various toxic and oxidative damages, and NRF2 activators thereby have efﬁcacy in cancer chemoprevention. Because NRF2 has a cytoprotective function, it can protect normal cells from carcinogens like an angel, but when the protective effect acts on cancer cells, it will give rise to invincible cancer cells and play a devilish role in tumor progression. Indeed, aberrant activation of NRF2 has been found in a variety of cancers that create a favorable environment for the proliferation and survival of cancer cells and leads to drug resistance, ultimately leading to the poor clinical prognosis of patients. Therefore, pharmacological inhibition of NRF2 signaling has emerged as a promising approach for cancer therapy. This review aims to compile the regulatory mechanisms of NRF2 and its double-edged role in cancer. In addition, we also summarize the research progress of NRF2 modulators, especially phytochemicals, in chemoprevention and cancer therapy. Keywords: Cancer therapy, Chemoprevention, NRF2, Phytochemicals 1. Discovery of NRF2 N RF2 (Nuclear factor erythroid 2-related factor 2), also known as Nuclear Factor, Erythroid 2 Like 2 (NFE2L2), was discovered as a widely expressed transcription factor belonging to the CNC (cap 'n' collar)-basic leucine zipper family [1,2]. In humans, NRF2 protein is composed of 605 amino acids and is encoded by the NFE2L2 gene located

FAQs

What is NRF2’s role in cellular protection and cancer risk?

NRF2 activation induces antioxidant proteins and phase 2 detoxifying enzymes that protect cells from toxic and oxidative damage. However, aberrant NRF2 activation in cancer cells can support tumor progression, survival, and drug resistance.

Why is targeting NRF2 considered a promising cancer therapy approach?

Because NRF2 can function as a double-edged regulator: while it protects normal cells, its protective effects in cancer cells can create favorable conditions for proliferation and poor clinical outcomes. Pharmacological inhibition of NRF2 signaling is highlighted as a promising strategy.

What does the review focus on besides general NRF2 mechanisms?

The review compiles regulatory mechanisms of NRF2 and summarizes research progress of NRF2 modulators, with special emphasis on phytochemicals in both chemoprevention and cancer therapy.

Sep 24, 2026

Uploaded by Aran