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Role of Nrf2/Keap1 Signaling Pathway in Human Diseases
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Role of Nrf2/Keap1 Signaling Pathway in Human Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 20910

Special Issue Editor

Dr. Eun-Hee Kim

E-Mail Website
Guest Editor
Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, 120 Haeryong-ro, Pocheon 11160, Korea
Interests: Nrf2; Keap1; reactive oxygen species; oxidative stress; inflammation; cancer; gastrointestinal tract; chemoprevention; cancer metabolism; metastasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The nuclear factor, erythroid 2-like transcription factor 2 (Nrf2), and its cytoplasmic repressor, kelch-like ECH-associated protein 1 (Keap1), regulate the expression of the antioxidant and cytoprotective genes so as to maintain redox homeostasis. The Nrf2/Keap1 pathway is an important signaling cascade responsible for the resistance of oxidative damage, exerts anti-inflammation and anticancer activity by regulating its multiple downstream cytoprotective genes, thereby plays a vital role in cell survival. Research in the molecular biology, biochemistry, and related basic fields of the Nrf2/Keap1 pathway are still very active, Nrf2-related research are expanding into more clinical areas such as cardiology, nephrology, endocrinology, and metabolism. Interestingly, in recent years, evidence is sccumulating that Nrf2 plays a contradictory role in cancers. Aberrant activation of Nrf2 promotes cancer cell proliferation by metabolic reprogramming and repression of cancer cell apoptosis, and contributes to the chemoresistance of cancer cells as well as inflammation-induced carcinogenesis. Therefore, understanding the role and regulatory molecular mechanism of Nrf2/Keap1 pathway in varous human diseases including cancer may be an effective strategy for the development of novel therapeutic approaches to varous disorders including cancer. In this Special Issue of International Journal of Molecular Sciences, “Role of Nrf2/Keap1 signaling pathway in human diseases”,  experts are invited to contribute original research papers or review articles will provide further insights on the role of Nrf2/Keap1 signaling pathway in human diseases.

Dr. Eun-Hee Kim
Guest Editor

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Keywords

  • Nrf2
  • Keap1
  • Reactive oxygen species
  • Oxidative stress
  • Redox signaling
  • Inflammation
  • Cancer
  • Chemoprevention
  • Chemoresistance
  • Proliferation
  • Apoptosis
  • Metastasis

Published Papers (4 papers)

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Research

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15 pages, 2135 KiB  
Article
Interdisciplinary Study of the Effects of Dipeptidyl-Peptidase III Cancer Mutations on the KEAP1-NRF2 Signaling Pathway
by Sara Matić, Ana Tomašić Paić, Sandra Sobočanec, Marija Pinterić, Goran Pipalović, Monika Martinčić, Mihaela Matovina and Sanja Tomić
Int. J. Mol. Sci. 2022, 23(4), 1994; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23041994 - 11 Feb 2022
Cited by 7 | Viewed by 1752
Abstract
Dipeptidyl peptidase III (DPP III) is associated with cancer progression via interaction with KEAP1, leading to upregulation of the KEAP1-NRF2 oxidative stress pathway. Numerous DPP III mutations have been found in human tumor genomes, and it is suggested that some of them may [...] Read more.
Dipeptidyl peptidase III (DPP III) is associated with cancer progression via interaction with KEAP1, leading to upregulation of the KEAP1-NRF2 oxidative stress pathway. Numerous DPP III mutations have been found in human tumor genomes, and it is suggested that some of them may alter affinity for KEAP1. One such example is the DPP III-R623W variant, which in our previous study showed much higher affinity for the Kelch domain of KEAP1 than the wild-type protein. In this work, we have investigated the effects of this mutation in cultured cells and the effects of several other DPP III mutations on the stability of KEAP1-DPP III complex using an interdisciplinary approach combining biochemical, biophysical and molecular biology methods with computational studies. We determined the affinity of the DPP III variants for the Kelch domain experimentally and by molecular modeling, as well as the effects of the R623W on the expression of several NRF2-controlled genes. We confirmed that the R623W variant upregulates NQO1 expression at the transcriptional level. This supports the hypothesis from our previous study that the increased affinity of the R623W variant for KEAP1 leads to upregulation of the KEAP1-NRF2 pathway. These results provide a new perspective on the involvement of DPP III in cancer progression and prognosis. Full article
(This article belongs to the Special Issue Role of Nrf2/Keap1 Signaling Pathway in Human Diseases)
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Review

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23 pages, 1093 KiB  
Review
An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases
by Emilia Zgorzynska, Barbara Dziedzic and Anna Walczewska
Int. J. Mol. Sci. 2021, 22(17), 9592; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179592 - 04 Sep 2021
Cited by 69 | Viewed by 6082
Abstract
Nrf2 is a basic region leucine-zipper transcription factor that plays a pivotal role in the coordinated gene expression of antioxidant and detoxifying enzymes, promoting cell survival in adverse environmental or defective metabolic conditions. After synthesis, Nrf2 is arrested in the cytoplasm by the [...] Read more.
Nrf2 is a basic region leucine-zipper transcription factor that plays a pivotal role in the coordinated gene expression of antioxidant and detoxifying enzymes, promoting cell survival in adverse environmental or defective metabolic conditions. After synthesis, Nrf2 is arrested in the cytoplasm by the Kelch-like ECH-associated protein 1 suppressor (Keap1) leading Nrf2 to ubiquitin-dependent degradation. One Nrf2 activation mechanism relies on disconnection from the Keap1 homodimer through the oxidation of cysteine at specific sites of Keap1. Free Nrf2 enters the nucleus, dimerizes with small musculoaponeurotic fibrosarcoma proteins (sMafs), and binds to the antioxidant response element (ARE) sequence of the target genes. Since oxidative stress, next to neuroinflammation and mitochondrial dysfunction, is one of the hallmarks of neurodegenerative pathologies, a molecular intervention into Nrf2/ARE signaling and the enhancement of the transcriptional activity of particular genes are targets for prevention or delaying the onset of age-related and inherited neurogenerative diseases. In this study, we review evidence for the Nrf2/ARE-driven pathway dysfunctions leading to various neurological pathologies, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, as well as amyotrophic lateral sclerosis, and the beneficial role of natural and synthetic molecules that are able to interact with Nrf2 to enhance its protective efficacy. Full article
(This article belongs to the Special Issue Role of Nrf2/Keap1 Signaling Pathway in Human Diseases)
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13 pages, 557 KiB  
Review
An Update on the Role of Nrf2 in Respiratory Disease: Molecular Mechanisms and Therapeutic Approaches
by Jooyeon Lee, Jimin Jang, Sung-Min Park and Se-Ran Yang
Int. J. Mol. Sci. 2021, 22(16), 8406; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168406 - 05 Aug 2021
Cited by 36 | Viewed by 3862
Abstract
Nuclear factor erythroid 2-related factor (Nrf2) is a transcriptional activator of the cell protection gene that binds to the antioxidant response element (ARE). Therefore, Nrf2 protects cells and tissues from oxidative stress. Normally, Kelch-like ECH-associated protein 1 (Keap1) inhibits the activation of Nrf2 [...] Read more.
Nuclear factor erythroid 2-related factor (Nrf2) is a transcriptional activator of the cell protection gene that binds to the antioxidant response element (ARE). Therefore, Nrf2 protects cells and tissues from oxidative stress. Normally, Kelch-like ECH-associated protein 1 (Keap1) inhibits the activation of Nrf2 by binding to Nrf2 and contributes to Nrf2 break down by ubiquitin proteasomes. In moderate oxidative stress, Keap1 is inhibited, allowing Nrf2 to be translocated to the nucleus, which acts as an antioxidant. However, under unusually severe oxidative stress, the Keap1-Nrf2 mechanism becomes disrupted and results in cell and tissue damage. Oxide-containing atmospheric environment generally contributes to the development of respiratory diseases, possibly leading to the failure of the Keap1-Nrf2 pathway. Until now, several studies have identified changes in Keap1-Nrf2 signaling in models of respiratory diseases, such as acute respiratory distress syndrome (ARDS)/acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and asthma. These studies have confirmed that several Nrf2 activators can alleviate symptoms of respiratory diseases. Thus, this review describes how the expression of Keap1-Nrf2 functions in different respiratory diseases and explains the protective effects of reversing this expression. Full article
(This article belongs to the Special Issue Role of Nrf2/Keap1 Signaling Pathway in Human Diseases)
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16 pages, 1024 KiB  
Review
The Role of NRF2/KEAP1 Signaling Pathway in Cancer Metabolism
by Moon-Young Song, Da-Young Lee, Kyung-Soo Chun and Eun-Hee Kim
Int. J. Mol. Sci. 2021, 22(9), 4376; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094376 - 22 Apr 2021
Cited by 59 | Viewed by 8116
Abstract
The nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also called Nfe2l2) and its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (KEAP1), are major regulators of redox homeostasis controlling a multiple of genes for detoxification and cytoprotective enzymes. The NRF2/KEAP1 pathway is a fundamental [...] Read more.
The nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also called Nfe2l2) and its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (KEAP1), are major regulators of redox homeostasis controlling a multiple of genes for detoxification and cytoprotective enzymes. The NRF2/KEAP1 pathway is a fundamental signaling cascade responsible for the resistance of metabolic, oxidative stress, inflammation, and anticancer effects. Interestingly, a recent accumulation of evidence has indicated that NRF2 exhibits an aberrant activation in cancer. Evidence has shown that the NRF2/KEAP1 signaling pathway is associated with the proliferation of cancer cells and tumerigenesis through metabolic reprogramming. In this review, we provide an overview of the regulatory molecular mechanism of the NRF2/KEAP1 pathway against metabolic reprogramming in cancer, suggesting that the regulation of NRF2/KEAP1 axis might approach as a novel therapeutic strategy for cancers. Full article
(This article belongs to the Special Issue Role of Nrf2/Keap1 Signaling Pathway in Human Diseases)
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