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<p>Nuclear factor erythroid 2–related factor 2 (NRF2) has emerged as a master regulator of cellular redox homeostasis and metabolic reprogramming in cancer. While traditionally known for its role in antioxidant defense, recent evidence highlights NRF2’s pivotal involvement in oncogenic metabolism, therapy resistance, and cell fate decisions. In cancer cells, persistent NRF2 activation upregulates cytoprotective genes, promoting proliferation by suppressing apoptosis and enhancing survival under stress conditions. The interplay between oxidative stress, detoxification pathways, and adaptive cellular responses forms a critical foundation for both tumor initiation and progression. Aberrant activation of these mechanisms contributes to genomic instability, increasing DNA mutation rates and cancer susceptibility. This review provides an integrated perspective on the canonical and non-canonical pathways governing NRF2 activation, with a focus on its intricate crosstalk with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). We propose a novel dual-axis model that stratifies NRF2 function based on tumor stage and redox status, capturing its context-dependent roles in tumorigenesis. Additionally, we explore the complementary role of NRF1, an ER-resident transcription factor that cooperates with NRF2 to maintain proteostasis and mediate stress resilience. Finally, we examine the therapeutic landscape of NRF2-targeted agents including ML385, PRL295, Omaveloxolone, and DHTI, highlighting their potential for therapeutic use tailored to tumor stage and cellular context.</p>

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The Central Role of NRF2 in Cancer Metabolism and Redox Signaling: Novel Insights into Crosstalk with ER Stress and Therapeutic Modulation

  • 期刊论文

  • 发表日期：

    2025年7月15日

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  • Amie N. Joof,
  • Ousman Bajinka,
  • Yan Zhou,
  • Fangyuan Ren,
  • Yurong Tan

摘要

Nuclear factor erythroid 2–related factor 2 (NRF2) has emerged as a master regulator of cellular redox homeostasis and metabolic reprogramming in cancer. While traditionally known for its role in antioxidant defense, recent evidence highlights NRF2’s pivotal involvement in oncogenic metabolism, therapy resistance, and cell fate decisions. In cancer cells, persistent NRF2 activation upregulates cytoprotective genes, promoting proliferation by suppressing apoptosis and enhancing survival under stress conditions. The interplay between oxidative stress, detoxification pathways, and adaptive cellular responses forms a critical foundation for both tumor initiation and progression. Aberrant activation of these mechanisms contributes to genomic instability, increasing DNA mutation rates and cancer susceptibility. This review provides an integrated perspective on the canonical and non-canonical pathways governing NRF2 activation, with a focus on its intricate crosstalk with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). We propose a novel dual-axis model that stratifies NRF2 function based on tumor stage and redox status, capturing its context-dependent roles in tumorigenesis. Additionally, we explore the complementary role of NRF1, an ER-resident transcription factor that cooperates with NRF2 to maintain proteostasis and mediate stress resilience. Finally, we examine the therapeutic landscape of NRF2-targeted agents including ML385, PRL295, Omaveloxolone, and DHTI, highlighting their potential for therapeutic use tailored to tumor stage and cellular context.