Cited by 795Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressBioactive Compounds and Antitumor Agents

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Small Molecule Modulators of Keap1‐ Nrf2‐ ARE Pathway as Potential Preventive and Therapeutic Agents

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Magesh, Sadagopan, Chen, Yu, Hu, Longqin·2012·Medicinal Research Reviews

DOI 10.1002/med.21257PMC PMC3393814

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Abstract

Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response elements (ARE) pathway represents one of the most important cellular defense mechanisms against oxidative stress and xenobiotic damage. Activation of Nrf2 signaling induces the transcriptional regulation of ARE-dependent expression of various detoxifying and antioxidant defense enzymes and proteins. Keap1-Nrf2-ARE signaling has become an attractive target for the prevention and treatment of oxidative stress-related diseases and conditions including cancer, neurodegenerative, cardiovascular, metabolic, and inflammatory diseases. Over the last few decades, numerous Nrf2 inducers have been developed and some of them are currently undergoing clinical trials. Recently, overactivation of Nrf2 has been implicated in cancer progression as well as in drug resistance to cancer chemotherapy. Thus, Nrf2 inhibitors could potentially be used to improve the effectiveness of cancer therapy. Herein, we review the signaling mechanism of Keap1-Nrf2-ARE pathway, its disease relevance, and currently known classes of small molecule modulators. We also discuss several aspects of Keap1-Nrf2 interaction, Nrf2-based peptide inhibitor design, and the screening assays currently used for the discovery of direct inhibitors of Keap1-Nrf2 interaction.

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2 retracted

Nuclear Import and Export Signals in Control of Nrf2
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Retracted
RETRACTED: Sulforaphane protects brains against hypoxic–ischemic injury through induction of Nrf2-dependent phase 2 enzyme
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“Sesquiterpenes such as zumberone (18)180 and isoalantolactone (19),181 and terpenoids containing α,β-unsaturated fragrant aldehydes182 such as perillaldehyde (20) and citral (21) were shown to induce Nrf2-mediated expression of detoxifying enzymes.”
Background
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“Sofalcone (6) is a synthetic derivative of a sophoradin chalconoid, found in herbs of Sophora tonkinensis, which is used as traditional Chinese medicine.”
Background
Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
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“Sesquiterpenes such as zumberone (18)180 and isoalantolactone (19),181 and terpenoids containing α,β-unsaturated fragrant aldehydes182 such as perillaldehyde (20) and citral (21) were shown to induce Nrf2-mediated expression of detoxifying enzymes.”
Background
Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
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“Investigation of ARE-inducing activities of monocyclic systems such as MCE-1 (27) and MCE5 (28) demonstrated that 27 was approximately twofold less potent than 26, but approximately tenfold more potent than 28.”
BackgroundInfluential
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Background
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Background
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BackgroundInfluential
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Background
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Background
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“Unfortunately, it has been difficult to develop specific and effective Nrf2 inhibitors since Nrf2 belongs to a big family of basic leucine zipper transcription factors,which are involved in the regulation of diverse and critical biological functions [42,50].”
Background
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“A research suggests that the suppression of Nrf2 and enhancement of Keap-1 induce the cellular susceptibility towards ROS, which promotes the inflammatory reaction or immune in the carcinogenesis process (Singh et al., 2006; Hayes & McMahon, 2009; Solis et al., 2010; Linker et al., 2011).”
BackgroundInfluential
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“Upon oxidative stress stimulation, Nrf2 quickly disassociates from Keap1, translocates into the nucleus, binds to small Maf proteins to form heterodimers, and interacts with ARE in the target genes, thereby regulating the transcription and translation of antioxidant genes [29].”
Background
New pectic polysaccharides from Codonopsis pilosula and Codonopsis tangshen: structural characterization and cellular antioxidant activities
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“HO-1 is a crucial antioxidant enzyme with a binding site of a promoter similar to that of ARE, thus being targeted by Nrf2 [34].”
BackgroundInfluential
Impact of NQO1 dysregulation in CNS disorders
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Dimethyl fumarate regulates histone deacetylase expression in astrocytes
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Acacia nilotica leaf improves insulin resistance and hyperglycemia associated acute hepatic injury and nephrotoxicity by improving systemic antioxidant status in diabetic mice
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Delayed treatment with oleanolic acid attenuates tubulointerstitial fibrosis in chronic cyclosporine nephropathy through Nrf2/HO-1 signaling
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“Nrf2 appears to function upon being released from its repressor Kelchlike ECH-associated protein 1 (Keap1) by sensing cytoplasmic oxidative stress or other specific chemical agents [6,7].”
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Chlorogenic acid supplementation alleviates dextran sulfate sodium (DSS)-induced colitis via inhibiting inflammatory responses and oxidative stress, improving gut barrier integrity and Nrf-2/HO-1 pathway
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N-Acetylcysteine Nanocarriers Protect against Oxidative Stress in a Cellular Model of Parkinson’s Disease
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Protective effect of Nrf2–ARE activator isolated from green perilla leaves on dopaminergic neuronal loss in a Parkinson's disease model
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Protective Effects of Caffeic Acid Phenethyl Ester (CAPE) and Novel Cape Analogue as Inducers of Heme Oxygenase-1 in Streptozotocin-Induced Type 1 Diabetic Rats
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“The transcription factor called Nrf2 (nuclear factor erythroid-derived 2) is referred to as the “master regulator” of the antioxidant response; it modulates the expression of hundreds of genes, including those with a promoter region containing an antioxidant response element (ARE) [19], such as heme oxygenase-1 (HO-1)…”
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Contrast media (meglumine diatrizoate) aggravates renal inflammation, oxidative DNA damage and apoptosis in diabetic rats which is restored by sulforaphane through Nrf2/HO-1 reactivation
Khaleel, S. A., Raslan, N. A., Alzokaky, A. A., Ewees, M. G., Ashour, A. A., Abdel‐Hamied, H. E., & Abd‐Allah, A. R. A. (2019) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2019.06.002 · Cited by 47
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“Nevertheless, the high potential of these compounds to react with other cysteine-containing proteins has raised safety concerns over their continuing use as therapeutic agents.(8) Therefore, the identification and design of new inhibitors to disrupt Keap1-Nrf2 protein–protein interaction represent an attractive novel…”
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Puerarin prevents cataract development and progression in diabetic rats through Nrf2/HO‑1 signaling
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Allisartan isoproxil attenuates oxidative stress and inflammation through the SIRT1/Nrf2/NF‑κB signalling pathway in diabetic cardiomyopathy rats
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Resveratrol dimers, nutritional components in grape wine, are selective ROS scavengers and weak Nrf2 activators
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The Nrf2-Keap1/ARE signaling pathway in aquatic animals
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SIRT6 protects retinal ganglion cells against hydrogen peroxide-induced apoptosis and oxidative stress by promoting Nrf2/ARE signaling via inhibition of Bach1
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Higher Circulating Trimethylamine N-oxide Sensitizes Sevoflurane-Induced Cognitive Dysfunction in Aged Rats Probably by Downregulating Hippocampal Methionine Sulfoxide Reductase A
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“ROS and electrophiles are known to react with KEAP1 cysteine residues, thereby preventing NRF2 ubiquitination and proteasomal degradation and promoting NRF2 nuclear accumulation [8].”
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Oleanolic Acid: A Promising Antioxidant—Sources, Mechanisms of Action, Therapeutic Potential, and Enhancement of Bioactivity
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“This enone motif is a known Michael acceptor, which can react with thiols of the Keap1 protein, activating Nrf2 and downstream antioxidant enzymes (like heme oxygenase-1) [89].”
Methylation of arginine by PRMT1 regulates Nrf2 transcriptional activity during the antioxidative response
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Novel Oxindole–Curcumin Hybrid Compound for Antioxidative Stress and Neuroprotection
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“The black line in Figure 1C represents promotion. antioxidant response element: ARE; Kelch-like ECH-associated protein 1: Keap1; nuclear factor erythroid 2-r lated factor 2: Nrf2; small musculoaponeurotic fibrosarcoma: sMAF; h me oxyg nase 1: HO-1; NADP (H) quinone dehydrogenase 1: NQO1; glutathione-S-transferases: GS…”
BackgroundInfluential
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Yang, X., Liu, X., Nie, Y., Zhan, F., & Zhu, B. (2023) · Virology Journal · doi:10.1186/s12985-023-02194-w · Cited by 50
3,4‐Dihydroxybenzalacetone Protects Against Parkinson's Disease‐Related Neurotoxin 6‐OHDA Through Akt/Nrf2/Glutathione Pathway
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“…conjugatedwith electron‐ withdrawing carbonyl groups) in the propene side chain and/or catechol‐derived oxidizable phenols of DBL directly inhibit the interaction of Kelch‐like ECH‐associated protein 1 (Keap) and Nrf2, leading to the translocation of Nrf2 to the nucleus [Magesh et al., 2012].”
Background
Daphnetin ameliorates 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis through Nrf-2-Keap1 and NF-κB pathways
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Exercise combined with a probiotics treatment alters the microbiome, but moderately affects signalling pathways in the liver of male APP/PS1 transgenic mice
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“Keap1/Nrf2/ARE pathway exerting a key role in cellular defense towards OS and xenobiotic damage (Magesh et al., 2012).”
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A Mechanistic Evaluation of Antioxidant Nutraceuticals on Their Potential against Age-Associated Neurodegenerative Diseases
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Jacquet, A. D. R., Timmers, M. A., Ma, S. Y., Thieme, A., McCabe, G. P., Vest, J. H. C., Lila, M. A., & Rochet, J. (2017) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2017.02.021 · Cited by 41
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Lycium ruthenicum Murr polysaccharide protects cortical neurons against oxygen-glucose deprivation/reperfusion in neonatal hypoxic-ischemic encephalopathy
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Protective Effects of Sulforaphane Preventing Inflammation and Oxidative Stress to Enhance Metabolic Health: A Narrative Review
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S-1-propenylmercaptocysteine protects murine hepatocytes against oxidative stress via persulfidation of Keap1 and activation of Nrf2
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Selenepezil, a Selenium-Containing Compound, Exerts Neuroprotective Effect via Modulation of the Keap1–Nrf2–ARE Pathway and Attenuates Aβ-Induced Cognitive Impairment in Vivo
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Authors: Magesh, S., Chen, Y., & Hu, L.
Affiliations: Rutgers, The State University of New Jersey (US)
Corresponding author: Hu, Longqin
ORCID: Chen, Yu
Hu, Longqin
Venue: Medicinal Research Reviews
Publisher: Wiley
Published: 2012-05
Volume: 32
Issue: 4
Pages: 687-726
ISSN: 0198-6325 (ISSN-L)
1098-1128
DOI: 10.1002/med.21257
PMC: PMC3393814
OpenAlex: W1767659454
Cited by: 760
References: 275
Citations by year: 2026: 30 · 2025: 39 · 2024: 52 · 2023: 61 · 2022: 69 · 2021: 58 · 2020: 85 · 2019: 81 · 2018: 54 · 2017: 63 · 2016: 41 · 2015: 56 · 2014: 42 · 2013: 28 · 2012: 1
FWCI: 3.79
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Medicinal Research Reviews (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (CA133791, CA125868, MH093197)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Keywords: Nrf2/Keap1 pathway, Nrf2, Keap1, antioxidant response element, small molecule modulators, Nrf2 inducers, Nrf2 inhibitors, oxidative stress, xenobiotic detoxification, antioxidant defense, cancer chemotherapy resistance, peptide inhibitors, Keap1-Nrf2 interaction
MeSH terms: Animals, Anti-Inflammatory Agents, Antineoplastic Agents, Antioxidants, Humans, Hypoglycemic Agents, Signal Transduction, Oxidative Stress, Neuroprotective Agents, Response Elements, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2

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Small Molecule Modulators of Keap1‐ Nrf2‐ ARE Pathway as Potential Preventive and Therapeutic Agents

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