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The Keap1-Nrf2 system and diabetes mellitus
Open accessAbstract
Nrf2 (NF-E2-related factor 2) plays a key role in the protection of vertebrates against environmental stress by contributing to the inducible expression of detoxification and antioxidant enzymes. Keap1 (Kelch-like ECH-associated protein 1) is a sensor for oxidative and electrophilic stresses. Keap1 also acts as an E3 ubiquitin ligase substrate-recognition subunit that specifically targets Nrf2. Keap1 causes Nrf2 to be degraded through the ubiquitin-proteasome pathway and thus ensures that Nrf2 is constitutively suppressed under unstressed conditions. Upon exposure to oxidative or electrophilic stress, Keap1 loses its ability to ubiquitinate Nrf2. Many lines of evidence have recently clarified that the Keap1-Nrf2 system also plays critical roles in the maintenance of cellular homeostasis. One of the most salient examples is the contribution of Keap1-Nrf2 to metabolic and energy-balance regulation. In particular, how the Keap1-Nrf2 system protects the body against diabetes mellitus and how perturbations in this system provoke the disease condition are now under intense investigation. This review will summarize the recent progress made in this area.
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“despite its beneficial role in cellular protection and cancer prevention, Nrf2 also has a harmful “dark side” in cancer [156].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [156]
Citations
Cites
Biochemistry and molecular cell biology of diabetic complications
Brownlee, M. (2001) · Nature · doi:10.1038/414813a · Cited by 9,107
Mechanisms linking obesity to insulin resistance and type 2 diabetes
Kahn, S. E., Hull, R. L., & Utzschneider, K. M. (2006) · Nature · doi:10.1038/nature05482 · Cited by 5,448
Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage
Nishikawa, T., Edelstein, D., Du, X. L., Yamagishi, S.-I., Matsumura, T., Kaneda, Y., Yorek, M. A., Beebe, D., Oates, P. J., Hammes, H.-P., et al. (2000) · Nature · doi:10.1038/35008121 · Cited by 4,277
Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., et al. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6943 · Cited by 3,999
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M. (1999) · Genes & Development · doi:10.1101/gad.13.1.76 · Cited by 3,634
Self-citationKobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224
The Nrf2 regulatory network provides an interface between redox and intermediary metabolism
Hayes, J. D., & Dinkova‐Kostova, A. T. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.02.002 · Cited by 2,210
H 2 O 2 , a Necessary Evil for Cell Signaling
Rhee, S. G. (2006) · Science · doi:10.1126/science.1130481 · Cited by 2,160
Changes in diabetes-related complications in the United States, 1990-2010
Gregg, E. W., Li, Y., Wang, J., Rios Burrows, N., Ali, M. K., Rolka, D., Williams, D. E., & Geiss, L. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1310799 · Cited by 1,749
Ishii, T., Itoh, K., Takahashi, S., Sato, H., Yanagawa, T., Katoh, Y., Bannai, S., & Yamamoto, M. P. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.21.16023 · Cited by 1,473
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Research works printed but not linked: 2
- Thimmulappa, 2002, Cancer Res., 62, 5196
- Chartoumpekis, 2013, Curr. Diabetes Rev., 9, 137
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Song, L., Li, Y., Zhan, H., Wu, L., Tang, L., Wang, X., & Deng, Q. (2026) · Journal of Natural Medicines · doi:10.1007/s11418-025-01968-6 · Cited by 2
Vargas-Mendoza, N., Sandoval-Gallegos, E. M., Madrigal‐Santillán, E., Morales-Martínez, M., Soriano-Ursua, M. A., Ángeles-Valencia, M., Morales‐González, Á., Portillo-Reyes, J., & Morales‐González, J. A. (2021) · Reference series in phytochemistry · doi:10.1007/978-3-030-45299-5_34-1 · Cited by 2
Antidiabetic plants, phytoconstituents, and nanoformulations for diabetes treatment
Ramteke, P. K., Jambhekar, H. A., Jambhekar, V. B., Kamthe, K. T., & Ghule, M. R. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95719-9.00016-1 · Cited by 2
Subba, R., Fasciolo, G., Geremia, E., Tomajoli, M. T. M., Petito, A., Carrella, S., Mondal, A. C., Napolitano, G., & Venditti, P. (2024) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2024.110101 · Cited by 2
Athari, S. Z., Mirzaei, F., Keyhanmanesh, ., Lotfi, H., Sajed, Y., Delkhosh, A., & Ghiasi, R. (2024) · PubMed Central · doi:10.22038/ijbms.2023.70416.15307 · Cited by 2
“It has been reported that Nrf2 in pancreatic beta cells in diabetes can suppress inflammation by modulating inflammation and the major systems of cellular protein degradation, namely proteasome and autophagy in pancreatic beta cells (50, 51).”
BackgroundFibromyalgia, Eating Disorders and Rehabilitation: The Nrf2 Link
Casale, R., Capodaglio, P., Petrikonis, K., Paladini, A., Sarzi-Puttini, P., & Bernatoniene, J. (2026) · Antioxidants · doi:10.3390/antiox15030364 · Cited by 1
“Nrf2 is a transcription factor that, when activated, binds to antioxidant response elements (ARE) in the promoter regions of over 500 genes, thereby coordinating the expression of antioxidant enzymes, phase II detoxification enzymes and cytoprotective proteins (Figure 2) [13,14,45].”
Ge, Y., Tang, Y. F., Lu, Y., Hou, S., Dai, Z., Xiong, R., Chen, S., Li, Y., & Xia, B. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1783967 · Cited by 1
“The significant downregulation of Keap1, along with the nuclear translocation of Nrf2 and the upregulation of its downstream target HO-1, provides robust evidence that POP functions as a potent Nrf2 activator (34, 35).”
10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC
Li, S., Shi, K., Huang, L., Li, Z., Qin, Z., Sun, Y., Qin, C., Wang, C., Li, H., Sun, J., et al. (2026) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2026.117828 · Cited by 1
Circadian rhythms, NRF2 signalling and redox homeostasis: A holy grail for a healthy life course?
Sutton, E., & Pekovic‐Vaughan, V. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.05.318 · Cited by 2
Vargas-Mendoza, N., Sandoval-Gallegos, E. M., Madrigal‐Santillán, E., Morales-Martínez, M., Soriano-Ursua, M. A., Ángeles-Valencia, M., Morales‐González, Á., Portillo-Reyes, J., & Morales‐González, J. A. (2022) · Reference series in phytochemistry · doi:10.1007/978-3-030-78160-6_34 · Cited by 1
Kimoloi, S. (2023) · International Journal of Sport Exercise and Health Research · doi:10.31254/sportmed.7208 · Cited by 1
“However, it is important to note that activation of Nrf2 signalling induces various intracellular antioxidant systems, which are known to effectively limit the levels of ROS and RNS [15, 26] .”
BackgroundBrassicaceae and Viral Diseases
Ross, I. A. (2024) · Springer eBooks · doi:10.1007/978-3-031-63681-3_14 · Cited by 1
The lesson to be learned from Broccoli and turmeric
Bhattacharyya, R., Singh, V., & Banerjee, D. (2018) · Integrative Food Nutrition and Metabolism · doi:10.15761/ifnm.1000212
“In diabetes mellitus and inflammatory disorders action of N2rf is expected to be beneficial [23,24].”
BackgroundTrisnawati, A., Anasrulloh, A., Rianawati, S. B., Khotimah, H., Ali, M., & Susetya, B. (2018) · MNJ (Malang Neurology Journal) · doi:10.21776/ub.mnj.2019.005.01.2
Kimchi and Asian fermented vegetables: candidates for the partial control of the COVID-19 pandemicPreprint
Bousquet, J. J., Antó, J. M., Czarlewski, W., Haahtela, T., Fonseca, S. C., Iaccarino, G., Blain, H., Park, H., Sheikh, A., Akdiş, C. A., et al. (2020) · doi:10.22541/au.159593999.91554264
FAIR and bias-free network modules for mechanism-based disease redefinitions
Hassan, A. (2021) · Research Publications (Maastricht University) · doi:10.26481/dis.20210707ah
NFE2L Regulation BY Endoplasmic Reticulum Stress
Bugno, M. (2015) · Carleton University's Institutional Repository (MacOdrum Library, Carleton University) · doi:10.22215/etd/2015-11159
Epigenetic modifications and regulations in gastrointestinal diseases
Bhattacharya, A. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-823931-5.00005-0
Chen, L., Xiao, G., Yu, Z., Huang, N., & Cheng, Y. (2024) · PubMed Central · doi:10.22038/ijbms.2024.79246.17166
Gluconephrotic Syndrome: A Comprehensive Review
Sharma, S., & Kalra, S. (2024) · Journal of the Association of Physicians of India · doi:10.59556/japi.72.0687
Wang, Z., Liu, S.-Y., Gao, M., Shen, Y., Sun, M., & Hao, S. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116251 · Cited by 2
Wang, Z., Liu, S., Gao, M., Shen, Y., Sun, M., & Hao, S. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116375
Caldeira, F. I. D., Silva, R. C. L., Martelli, M. G. G., Nicchio, I. G., Orrico, S. R. P., Cirelli, J. A., Cerri, E. S., Cerri, P. S., Leite, F. R. M., & Scarel‐Caminaga, R. M. (2026) · Biomedicines · doi:10.3390/biomedicines14040742
“Additionally, these substrates trigger a positive signaling cascade, activating NF-E2-related factor 2 and Kelch-like ECH-associated protein (Nrf2-Keap1), which are responsible for the production of antioxidant enzymes, including superoxide dismutase (SOD) [23].”
A review on Nrf2 and antioxidant metalloproteins
Hossain, A. M. S., Qudratovna, Q. M., Kholnazarov, B., Odaka, A., Nakane, D., & Akitsu, T. (2026) · European Journal of Chemistry · doi:10.5155/eurjchem.17.2.176-187.2773
Costa, V. B., de Godoi, M. A., Camilli, Â. C., Nogueira, I. R. G., dos Santos, V. C. E., Ramos, L. N., Siqueira, J. S., Corrêa, C. R., & Guimarães, M. R. (2026) · Journal of Periodontal Research · doi:10.1111/jre.70158
Malekinia, F., Ahangarpour, A., Hoseinynejad, K., Mard, S. A., Radan, M., & Nejaddehbashi, F. (2026) · Endocrinology Diabetes & Metabolism · doi:10.1002/edm2.70304
Wang, Y., Cao, M., Liu, Z., Wang, Z., Fu, J., Wang, H., Xu, Y., Wu, J., & Pi, J. (2026) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2026.118068
Filfilan, W. M., & El‐Beeh, M. E. (2026) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2026.122467
Taşci, S. Ç., & Bayraktar, B. (2026) · Antioxidants · doi:10.3390/antiox15111376
Metadata
- Authors
- Uruno, A., Yagishita, Y., & Yamamoto, M.
- Affiliations
- Tohoku University (JP)
- Corresponding author
- Uruno, Akira
- Yamamoto, Masayuki
- Venue
- Archives of Biochemistry and Biophysics
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 566
- Pages
- 76-84
- ISSN
- 0003-9861 (ISSN-L)
- OpenAlex
- W2091259533
- Cited by
- 231
- References
- 109
- Citations by year
- 2026: 15 · 2025: 7 · 2024: 19 · 2023: 20 · 2022: 26 · 2021: 23 · 2020: 28 · 2019: 24 · 2018: 20 · 2017: 13 · 2016: 16 · 2015: 20
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Archives of Biochemistry and Biophysics (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Science, Sports and Culture
- Create Revolutionary Technological Seeds for Science and Technology Innovation program (CREST) of the Japanese Technology Agency
- Japan Society for the Promotion of Science (24249015, 90396474, 26893008)
- Takeda Foundation
- Naito Foundation
- Japanese Foundation for Applied Enzymology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- Keap1, Nrf2, diabetes mellitus, oxidative stress, electrophilic stress, ubiquitin-proteasome system, E3 ubiquitin ligase, antioxidant defense, metabolic homeostasis, energy balance
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Animals, Diabetes Mellitus, Type 2, Gene Expression Regulation, Humans, Signal Transduction, Oxidative Stress, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Intracellular Signaling Peptides and Proteins, Insulin-Secreting Cells, NF-E2-Related Factor 2, Ubiquitination, Proteolysis
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