Modulating NRF2 in Disease: Timing Is Everything

Abstract

The transcription factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) is a central regulator of redox, metabolic, and protein homeostasis that intersects with many other signaling cascades. Although the understanding of the complex nature of NRF2 signaling continues to grow, there is only one therapeutic targeting NRF2 for clinical use, dimethyl fumarate, used for the treatment of multiple sclerosis. The discovery of new therapies is confounded by the fact that NRF2 levels vary significantly depending on physiological and pathological context. Thus, properly timed and targeted manipulation of the NRF2 pathway is critical in creating effective therapeutic regimens. In this review, we summarize the regulation and downstream targets of NRF2. Furthermore, we discuss the role of NRF2 in cancer, neurodegeneration, and diabetes as well as cardiovascular, kidney, and liver disease, with a special emphasis on NRF2-based therapeutics, including those that have made it into clinical trials.

Keywords: KEAP1; NRF2; cancer; clinical trials; disease; therapeutics.

Figure 1. Key discoveries in the NRF2 field.

Timeline depicting important discoveries in the NRF2 field over the past four decades.

Figure 2. Regulation of NRF2 and possible modes of activation.

Schematic representation of NRF2 modes of regulation. NRF2 is regulated at the post-transcriptional and post-translational level, as well as via epigenetic factors and interaction with other signaling pathways. Modulation of NRF2 protein levels can be achieved through activation or inhibition of the KEAP1-CUL3-RBX1 complex, SCF-β-TrCP complex, or HRD1. Electrophilic/oxidative modification of key cysteines, competitive binding of ETGE containing proteins, protein-protein interaction inhibitors, increased levels of p62/SQSTM1, mTOR inhibitors, and CUL3-Ring E3 ligase (CRL) inhibitors (i.e. MLN4924), can all disrupt the KEAP1-NRF2 interaction. Hypermethylation of the KEAP1 promoter can also increase expression of NRF2. The SCF/β-TrCP-NRF2 interaction can be modulated by insulin/growth factors, or GSK3-β, CRL, PI3K-AKT-PKC, mTOR, ERK/p38-MAPK, and WNT inhibitors. Inhibitors of HRD1 (i.e. LS-102) could be utilized to prevent ER-stress associated degradation of NRF2.

Figure 3. Cellular pathways driven by NRF2 target genes.

NRF2 heterodimerizes with sMAF proteins to initiate the transcription of ARE-containing target genes. Verified NRF2 target genes are involved in proteasome assembly, autophagy, prevention of apoptosis, maintaining redox balance, lipid and carbohydrate metabolism, heme metabolism, iron homeostasis, all three phases of drug/xenobiotic metabolism, transcriptional regulation of other transcription factors, and DNA repair. Representative target genes are included in parentheses below each transcriptional response.

Figure 4. Targeting NRF2 in disease is time and expression level dependent.

Graphical representation of NRF2 activators/inhibitors, and the current treatment options based on NRF2 levels in cancer and other chronic diseases. A number of NRF2 activators and inhibitors have been characterized that could be developed into translational therapeutics. The white box outlines therapies that have made it into clinical trials. DMF (Tecfidera), the only FDA approved drug, is indicated in bold. NRF2 levels and treatment possibilities vary depending on the timing and stage of disease. NRF2 activators are thought to provide the most therapeutic benefit prior to cancer initiation or onset of neurodegenerative or chronic inflammatory diseases. Some diseases, such as diabetes, cardiovascular disease, prostate cancer, inflammatory diseases, and post-initiation/early stage cancer have been reported to have either low or high levels of NRF2 depending on the context. Treatment options following onset of disease target NRF2 to intervene and prevent/delay progression. Many cancer types exhibit constitutively high levels of NRF2. For diseases where high levels of NRF2 are having a deleterious effect, an NRF2 inhibitor or adjuvant approach would be most effective. Cancers and late stage diseases with high levels of NRF2 are generally associated with poor prognosis, and treatments at this stage are designed to mitigate symptoms and enhance the efficacy of other therapies.