Abstract
The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) plays a critical role in the maintenance of cellular redox and metabolic homeostasis, as well as the regulation of inflammation and cellular detoxication pathways. The contribution of the NRF2 pathway to organismal homeostasis is seen in many studies using cell lines and animal models, raising intense attention towards targeting its clinical promise. Over the last three decades, an expanding number of clinical studies have examined NRF2 inducers targeting an ever-widening range of diseases. Full understanding of the pharmacokinetic and pharmacodynamic properties of drug candidates rely partly on the identification, validation, and use of biomarkers to optimize clinical applications. This review focuses on results from clinical trials with four agents known to target NRF2 signaling in preclinical studies (dimethyl fumarate, bardoxolone methyl, oltipraz, and sulforaphane), and evaluates the successes and limitations of biomarkers focused on expression of NRF2 target genes and others, inflammation and oxidative stress biomarkers, carcinogen metabolism and adduct biomarkers in unavoidably exposed populations, and targeted and untargeted metabolomics. While no biomarkers excel at defining pharmacodynamic actions in this setting, it is clear that these four lead clinical compounds do touch the NRF2 pathway in humans.
Highlights
The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) plays a critical role in the maintenance of cellular redox and metabolic homeostasis, as well as the regulation of inflammation and cellular detoxication pathways
While this review focuses on biomarkers likely related to NRF2 action, because of their reactivity with thiols all these agents affect multiple targets and pathways in cells
It is evident that other modes of action contribute to the molecular responses to SFN in animals and humans [119,197,198]. Such polypharmacy may well contribute to the efficacy of the agent in disease prevention and mitigation but obfuscates the value of specific pharmacodynamic biomarkers in the clinical development and evaluation of SFN—perhaps even more so, because unlike the situation with triterpenoids (e.g., CDDO-Im and CDDO-Me), where there appears to be a hierarchical activation of targets/pathways with increasing dose [62], it is more likely that the multiple targets of SFN are activated at similar concentrations [198]
Summary
It has been more than 20 years since the initial molecular description of the Keap1-Nrf signaling pathway, wherein it was recognized as an adaptive response pathway to exogenous [1], and later as an adaptive response pathway to endogenous stresses [2]. 2 (NRF2) is a transcription factor that regulates the expression of over 300 target genes with roles in antioxidant and anti-inflammatory actions, electrophile detoxication, cell metabolism, proliferation and differentiation, and general cytoprotection. In the presence of oxidative stress or inducers, which are often electrophiles, key “sensor” cysteine thiol groups on KEAP1 are modified, disrupting the degradation process and allowing for nascent. An additional feature is the extensive crosstalk between NRF2 and other transcription factor signaling pathways, allowing for further fine-tuning of physiological responses to stress. There are excellent reviews that document the historic milestones in the characterization of the pathway, the molecular mechanisms governing the functions of KEAP1 and NRF2, as well as their roles in physiology and pathology [3,4,5,6]
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