The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?

**Background:** The nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor that regulates cellular antioxidant systems in response to oxidative stress by governing the expression of genes encoding antioxidant enzymes. NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) have been the focus of numerous investigations to elucidate whether NRF2 suppresses tumor promotion or conversely exerts pro-oncogenic effects. This review article examines the multifaceted roles of NRF2 in both cancer prevention and promotion, including its involvement in dysregulated cell proliferation, metabolic remodeling, resistance to apoptosis, tumor immunology, cancer stem cells, metastasis, and long non-coding RNAs (LncRNAs). The review also addresses the advantages, disadvantages, and limitations associated with modulating NRF2 therapeutically in cancer treatment.

**Methods:** This is a narrative review article that synthesizes findings from a wide range of published studies on NRF2 biology and its role in cancer. The authors discuss the structure and function of NRF2, including its seven conserved Neh domains (Neh1-7), mechanisms of activation and inhibition (canonical and non-canonical pathways), and the genes regulated by NRF2 (antioxidant proteins, NADPH-regenerating enzymes, cytoprotective proteins, phase 1 and 2 enzymes, transport proteins, chaperone proteins, and transcription factors). The review also covers the dual role of NRF2 in cancer, its pro-oncogenic functions, and its impact on cell proliferation, tumor metabolism, cell death, tumor immunology, LncRNAs, phase separation, cancer stem cells, and metastasis. Additionally, the authors discuss NRF2 modulators (activators and inhibitors) and their therapeutic implications.

**Key Results:** The review highlights several key findings from the literature: - NRF2 knockout mice exhibit markedly lower basal and inducible expression of detoxification and antioxidant genes and increased sensitivity to various stressors, including cigarette smoke. - Liver-specific KEAP1 conditional knockout mice show high resistance to acetaminophen, even at lethal doses, due to NRF2 activation promoting GSH synthesis. - Constitutive activation of NRF2 contributes to chemotherapy resistance in cancer cells, which can be counteracted by siRNA targeting NRF2. - Mutations in KEAP1 and NRF2 are common in many cancers and are associated with poor prognosis. Primary mutations affect binding domains (Kelch, DLG, ETGE motifs), leading to NRF2 accumulation and overexpression of ARE-mediated genes, including MRP efflux pumps. - NRF2 regulates cancer cell proliferation by transcriptionally activating key proteins such as nephronectin (NPNT), bone morphogenetic protein receptor 1A (BMPR1A), insulin-like growth factor 1 (IGF1), integrin beta chain-2 (ITGB2), platelet-derived growth factor C (PDGFC), vascular endothelial growth factor C (VEGFC), and Jagged 1 protein (JAG1). - NRF2 plays a role in enhancing glutaminolysis, nucleotide metabolism, and upregulation of metabolic enzymes within the pentose phosphate pathway (PPP), leading to NADPH production. - NRF2 confers resistance to ferroptosis through target genes such as GPX4 and xCT. - NRF2 activation in cancer cells can influence macrophage polarization toward M2-like populations and protect immunosuppressive myeloid-derived suppressor cells (MDSCs) from high ROS levels. - Patients with lung squamous cell carcinoma exhibiting NRF2 activation have shown limited responses to PD-L1 immunotherapy. - The NRF2 activator sulforaphane induces ROS generation, GSH depletion, and secretion of Th17 cytokines in human T cells. - The NRF2 inhibitor brusatol has demonstrated the capability to suppress metastasis and enhance sensitivity to chemotherapy in various animal models of cancer. - Long-term supplementation with NAC and vitamin E in a KRAS-driven lung cancer model promoted metastasis, attributed to stabilization of BACH1.

**Clinical Implications:** The dual role of NRF2 in cancer presents both opportunities and challenges for therapeutic intervention. NRF2 activators hold potential as chemopreventive agents, particularly in early-stage cancer, by protecting healthy cells from oxidative stress and carcinogens. However, in advanced cancers, NRF2 activation can promote tumor progression, chemotherapy resistance, and metastasis, making NRF2 inhibitors a promising strategy for anti-cancer therapy. The review emphasizes that the therapeutic utility of NRF2 modulators depends on the specific context, including tumor histotype, stage, genetic background, and treatment protocols. Currently, no specific inhibitor targeting NRF2 has been developed, and many existing modulators lack specificity or have off-target effects. Further research is needed to understand the precise mechanisms of NRF2 regulation and to develop more selective and effective NRF2-targeted therapies. The complex interplay between NRF2, ROS, and immune cells also requires careful consideration to avoid impairing anti-tumor immune responses.