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Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways
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In most tissues, cells are exposed to frequent changes in levels of oxidative stress and inflammation. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and nuclear factor-κB (NF-κB) are the two key transcription factors that regulate cellular responses to oxidative stress and inflammation respectively. Pharmacological and genetic studies suggest that there is functional cross-talk between these two important pathways. The absence of Nrf2 can exacerbate NF-κB activity leading to increased cytokine production, whereas NF-κB can modulate Nrf2 transcription and activity, having both positive and negative effects on the target gene expression. This review focuses on the potentially complex molecular mechanisms that link the Nrf2 and NF-κB pathways and the importance of designing more effective therapeutic strategies to prevent or treat a broad range of neurological disorders.
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“Lack of Nrf2 activity can exacerbate NF-κB signaling, leading to increased cytokine production; alternatively, NF-κB can modulate Nrf2 activity, having both positive and negative effects on target gene expression [152, 153].”
From Air pollution and children’s health—a review of adverse effects associated with prenatal exposure from fine to ultrafine particulate matter (2021) · cites this paper as [152]
In the citing paper
“Competition of Nrf2 and NF-κB at DNA binding level is one of the anti-inflammatory mechanisms of Nrf2 (60, 61).”
From Melatonin Attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 Inflammasome Activation Through the SIRT1/Nrf2 Pathway (2019) · cites this paper as [60]
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“Key antioxidant transcription factors activated in response to ROS include NF-κB and Nrf2 [30, 31].”
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“Further, evidence exists that suggest that apart from the attenuation of ROs, Nrf2 can regulate the inflammatory cascade by directly inhibiting signalling of NF-κB and pro-inflammatory markers while activating anti-inflammatory mediators (Wardyn et al .”
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“After 6-h exposure, a significant increase in HO-1 expression is observed, which persists after a longer exposure of 18 h. Exper - iments on various models have shown that increased HO-1 expression mediated by activated Nrf2 can lead to inhibition of NF-κB signaling [11,13].”
Su, C., Liu, Z., Liu, L., Xiong, Z., Xu, T., Zhang, S., Chen, Y., & Jiang, Y. (2024) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-024-03148-x · Cited by 2
“According to research by Wardyn et al. (2015), Keap1 may function as a molecular switch for Nrf2 in response to oxidative stress.”
Ahmed, O. M., Mosa, N. M., & Abou-Seif, H. S. (2024) · Egyptian Pharmaceutical Journal · doi:10.4103/epj.epj_54_24 · Cited by 2
Effect of thymoquinone on NRF2/NF-kB/MAPK pathway in methotrexate-induced rat testis injury.
Kaymak, E., Ceylan, T., Akın, T., Kuloğlu, N., Sayan, M., Değer, N., Önal, E., Yıldırım, A. B., & Karabulut, D. (2024) · PubMed Central · doi:10.22038/ijbms.2024.77714.16813 · Cited by 3
Zhao, J., Zhang, Q., & Hao, X. (2024) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.14105 · Cited by 2
“24,45 In this experimental study, we explored the effects of syringin on the multifaceted transcription factor NF-κ B signalling in colon tissues.”
Demir, E. A., Demir, S., Usta, Z. T., Alemdar, N. T., Menteşe, A., & Aliyazıcıoğlu, Y. (2025) · South African Journal of Botany · doi:10.1016/j.sajb.2025.02.006 · Cited by 2
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“…genes, and recruits RNA polymerase and transcriptional machinery to up-regulate the expression of antioxidant and cytoprotective genes, such as glutamate-cysteine ligase catalytic subunit ( GCLC ) (Mapuskar et al. 2023; Mirzaei et al. 2021; Ammal Kaidery et al. 2019; Itoh et al. 2004).”
The Beneficial Effects of a N-(1-Carbamoyl-2-phenyl-ethyl) Butyramide on Human Keratinocytes
Oglio, F., Coppola, S., Agizza, A., Masino, A., Luongo, C., Santillo, R. D., D’Auria, L., Russo, R., Neri, I., Grumetto, L., et al. (2025) · Pharmaceuticals · doi:10.3390/ph18040517 · Cited by 2
Guo, N., Huang, W., Huang, J., Liu, Y., Zhu, K., & Gao, W. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1588968 · Cited by 4
Yang, J., Liu, Y., Hu, W., Wang, Y., Chen, R., Xu, D., Liu, L., Zheng, L., Liu, B., Fan, Q., et al. (2025) · Poultry Science · doi:10.1016/j.psj.2025.105882 · Cited by 2
Ding, L.-L., Li, X., Guo, Y., Zhou, F., & Deng, D. Y. B. (2025) · Neuroscience Bulletin · doi:10.1007/s12264-025-01488-z · Cited by 2
“Deficiency of Nrf2 enhances NF-κB p65 activity, leading to the production of inflammatory mediators, while NF-κB p65 can modulate the transcription and activity of Nrf2, thereby influencing the expression of Nrf2 target genes [22, 23].”
Troxerutin Potentiated Temozolomide Induced Antitumor Effect in 2D and 3D Glioblastoma Models
Mannino, D., Calcaterra, E., Scuderi, S. A., Caffo, M., Luca, F. D., Catalfamo, A., Casili, G., & Paterniti, I. (2025) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70862 · Cited by 2
“Studies have reported that NRF2 suppresses tumorigenesis via transcriptionally activating the cytoprotective genes NAD(P)H Quinone Oxidoreductase I (NQO1) and HO-1 [45].”
Neuroinflammatory processes and oxidative stress
Clemons, T. A., Jelks, N. O., Vance, L. M., & Williams, K. S. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-817780-8.00003-7 · Cited by 2
Is there a place for anti-inflammatory therapy in COVID-19?
Yew, W. W., Chang, K. C., & Chan, D. P. C. (2020) · Journal of Thoracic Disease · doi:10.21037/jtd-20-2155 · Cited by 2
“Respiratory virus infections can trigger oxidative stress, through induction of enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, in host cells, generating reactive oxygen species (ROS).”
BackgroundInfluentialLee, J.-I., & Chung, M. (2021) · Journal of the Korean Society of Food Science and Nutrition · doi:10.3746/jkfn.2021.50.12.1282 · Cited by 2
Shahrani, M. M. A., Abohassan, M., Gahtani, R. M., Alshahrani, M. Y., Suliman, M., Ahmad, I. S., & Saeed, M. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2294377 · Cited by 2
“In addition, it has been shown that the lack of Nrf2 could exacerbate NF-j B activity, resulting in heightened cytokine production and conversely (Wardyn et al., 2015).”
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
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“Indeed, it is well-known that SFN is an effective activator of the transcription factor NRF2 (nuclear factor erythroid 2-related factor 2), which can modulate key components of the cellular defense processes, operating on redox- and inflammation-regulating gene expression via activation of the antioxidant responsive e…”
BackgroundExtracellular Hsp90α Detoxifies β-Amyloid Fibrils Through an NRF2 and Autophagy Dependent PathwayPreprint
Murshid, A., Lang, B. J., Borges, T. J., Okusha, Y., Doshi, S., Yasmine, S., Clark, J., Choudhury, R., Ang, L., Woodbury, M. E., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.16.440151 · Cited by 2
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Jiang, X. M., Wang, Z., Wang, L., Wang, Y., Zhao, L., & Jiang, H. (2025) · PLoS ONE · doi:10.1371/journal.pone.0321121 · Cited by 1
Nrf2: A Promising Therapeutic Target for Glucocorticoid-Resistant Chronic Rhinosinusitis
Wang, Y., & Yang, Y. (2025) · Clinical and Experimental Otorhinolaryngology · doi:10.21053/ceo.2024.00373 · Cited by 1
“[56,57] Inflammasome regulation Nrf2 inhibited the expression of genes involved in inflammasome assembly, including NLRP3, Caspase-1, IL-1 β and IL-18.”
Taştemur, Ş., Eki̇ci̇, M., Mendĭl, A. S., Özkaraca, M., & Ataseven, H. (2025) · Asian Biomedicine · doi:10.2478/abm-2025-0006 · Cited by 1
“Nfr2 activation reduces COX-2, iNOS, and TNF-α production, affecting NF-κ B activity [46].”
Jayan, S., John, J., Madhav Manoj, K., Thulasidharan, M. U., Rahul, R. S., Deepak, D. R., & Krishnan, V. (2025) · Archives of Oral Biology · doi:10.1016/j.archoralbio.2025.106345 · Cited by 1
Metadata
- Authors
- Wardyn, J. D., Ponsford, A. H., & Sanderson, C. M.
- Affiliations
- University of Liverpool (GB)
- Corresponding author
- Sanderson, Christopher M.
- Venue
- Biochemical Society Transactions
- Publisher
- Portland Press Ltd.
- Published
- 2015-08-01
- Volume
- 43
- Issue
- 4
- Pages
- 621-626
- ISSN
- 0300-5127 (ISSN-L)
- 1470-8752
- PMC
- PMC4613495
- OpenAlex
- W2133584350
- Cited by
- 1,200
- References
- 53
- Citations by year
- 2026: 139 · 2025: 131 · 2024: 117 · 2023: 145 · 2022: 165 · 2021: 154 · 2020: 124 · 2019: 95 · 2018: 68 · 2017: 44 · 2016: 15 · 2015: 1
- FWCI
- 4.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Society Transactions (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (096564/Z/11/Z)
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (1222890, BB/J014516/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- Nrf2, NF-κB, oxidative stress, inflammation, cytokine production, neurological disorders, treatment options
- MeSH terms
- Animals, Gene Expression Regulation, Humans, Nervous System Diseases, Signal Transduction, Cytokines, NF-kappa B, Oxidative Stress, NF-E2-Related Factor 2
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