NF-κB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK
Open accessAbstract
Constitutively activated NF-kappaB occurs in many inflammatory and tumor tissues. Does it interfere with anti-inflammatory or anti-tumor signaling pathway? Here, we report that NF-kappaB p65 subunit repressed the Nrf2-antioxidant response element (ARE) pathway at transcriptional level. In the cells where NF-kappaB and Nrf2 were simultaneously activated, p65 unidirectionally antagonized the transcriptional activity of Nrf2. In the p65-overexpressing cells, the ARE-dependent expression of heme oxygenase-1 was strongly suppressed. However, p65 inhibited the ARE-driven gene transcription in a way that was independent of its own transcriptional activity. Two mechanisms were found to coordinate the p65-mediated repression of ARE: (1) p65 selectively deprives CREB binding protein (CBP) from Nrf2 by competitive interaction with the CH1-KIX domain of CBP, which results in inactivation of Nrf2. The inactivation depends on PKA catalytic subunit-mediated phosphorylation of p65 at S276. (2) p65 promotes recruitment of histone deacetylase 3 (HDAC3), the corepressor, to ARE by facilitating the interaction of HDAC3 with either CBP or MafK, leading to local histone hypoacetylation. This investigation revealed the participation of NF-kappaB p65 in the negative regulation of Nrf2-ARE signaling, and might provide a new insight into a possible role of NF-kappaB in suppressing the expression of anti-inflammatory or anti-tumor genes.
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Decreased levels of Nrf2, a transcription factor negatively regulated by NF-κB and involved in antioxidant response mechanisms, have been reported in brains of Alzheimer's disease patients.
“In addition, decreased levels of Nrf2, a transcription factor negatively regulated by NF-κB (Liu et al., 2008) that is involved in antioxidants response mechanisms (Nair et al., 2008), have been reported in the brains of AD patients (Ramsey et al., 2007).”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Liu et al., 2008
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The Role of Reactive Oxygen Species in Arsenic Toxicity
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“Liu et al. demonstrated that NF-κ B p65 subunit repressed the bene fi cial effects of Nrf2 by promoting the localisation of transcription repressors, histone deacetylases with Nrf2/ARE and sequestering coactivators like CREB binding protein (CBP) [12].”
InfluentialCanonical and non-canonical mechanisms of Nrf2 activation
Silva‐Islas, C. A., & Maldonado, P. D. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.06.013 · Cited by 393 · see citing works
“p65 competes with Nrf2 for CBP binding, decreasing Nrf2 transcriptional activation [57], whereas MafG homodimer also decreases Nrf2 transcriptional activity by competing for ARE binding [7].”
NRF2-regulation in brain health and disease: Implication of cerebral inflammation
Sandberg, M., Patil, J., D’Angelo, B., Weber, S. G., & Mallard, C. E. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.11.004 · Cited by 389 · see citing works
“interaction of and CBP or MafK, causing local histone hypoacetylation and down-regulation of NRF2-ARE signaling (78).”
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“That mechanism dampens the Nrf2 signalling pathway activation and consequently antioxidant response [91,92].”
BackgroundEnvironmental toxicity, redox signaling and lung inflammation: The role of glutathione
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Catechins and Their Therapeutic Benefits to Inflammatory Bowel Disease
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“The protein level of Nrf2 was significantly escalated in the AcEGCG-treated mucosa dose-dependently than the control, depending on histone acetyltransferase (CBP/p300) activity, owing to the NF-κB inactivation and ERK (p44/42) MAPK phosphorylation.”
BackgroundEndo, H., Niioka, M., Kobayashi, N., Tanaka, M., & Watanabe, T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063388 · Cited by 335 · see citing works
Dissecting the Crosstalk Between Nrf2 and NF-κB Response Pathways in Drug-Induced Toxicity
Gao, W., Guo, L., Yang, Y., Wang, Y., Xia, S., Gong, H., Zhang, B., & Yan, M. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.809952 · Cited by 328 · see citing works
“, histone deacetylases (HDACs)) (Liu et al., 2008) (Figure 2B).”
BackgroundWang, L., & He, C.-Q. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.967193 · Cited by 352 · see citing works
Lin, W., Wu, R. T., Wu, T., Khor, T.-O., Wang, H., & Kong, A. T. (2008) · Biochemical Pharmacology · doi:10.1016/j.bcp.2008.07.036 · Cited by 324 · see citing works
“Given the fact that SFN at high concentration displayed a moderate inhibition in LPS-stimulated Nrf2(−/−) peritoneal macrophages, it is possible that SFN might impact AP-1 activity, which is not related to Nrf2-ARE pathway.”
BackgroundNuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway
Yu, M., Li, H., Liu, Q., Liu, F., Tang, L., Li, C., Yuan, Y., Zhan, Y., Xu, W., Li, W., et al. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.01.014 · Cited by 319 · see citing works
Molecular Basis of Electrophilic and Oxidative Defense: Promises and Perils of Nrf2
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“Many ARE inducers, including oltipraz, sulforaphane, and lately triterpenoids, have now been shown capable of both inducing ARE-dependent genes and inhibiting inflammatory response (Dinkova-Kostova et al., 2005; Killeen et al., 2006; Talalay et al., 2007; Liu et al., 2008b; Honda et al., 2011).”
Bao, L., Li, J., Zha, D., Zhang, L., Gao, P. H., Yao, T., & Wu, X. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.11.021 · Cited by 308 · see citing works
Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis
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The Role of Nrf2 Activity in Cancer Development and Progression
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“P65 overexpression is induced by NF-κB signaling [115].”
BackgroundLagoumtzi, S. M., & Chondrogianni, N. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.05.003 · Cited by 279 · see citing works
Wu, X., Huang, X., Chen, R.-R., Tang, L., Ye, H., Xie, W., Huang, Z., & Cao, G. (2019) · Inflammation · doi:10.1007/s10753-019-01085-z · Cited by 276 · see citing works
Proteostasis, oxidative stress and aging
Korovila, I., Hugo, M., Castro, J. P., Weber, D., Höhn, A., Grune, T., & Jung, T. (2017) · Redox Biology · doi:10.1016/j.redox.2017.07.008 · Cited by 274 · see citing works
Shaping the Nrf2-ARE-related pathways in Alzheimer’s and Parkinson’s diseases
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“Complementarily, there is a competition between NRF2 and NF‐κB‐p65 subunit to bind the transcriptional co‐activator CBP (CREB‐binding protein)–p300 complex, which enhances gene transcription by direct NRF2 or p65 acetylation and potentiates the activation of the antioxidant response or the pro‐inflammatory pathway, re…”
BackgroundBoesch, C., Łoboda, A., Wagner, A. E., Stachurska, A., Józkowicz, A., Dulak, J., Döring, F., Wolffram, S., & Rimbach, G. H. (2010) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2010.02.008 · Cited by 263 · see citing works
“There is cross-talk between the transcription factors NFκB and Nrf2 as far as inflammatory gene expression is concerned [34,35].”
BackgroundEpigenetic regulation of Keap1-Nrf2 signaling
Guo, Y., Yu, S., Zhang, C., & Kong, A. T. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.013 · Cited by 261 · see citing works
“Specifically, p65 enhances the interaction of HDAC3 with MafK (a known dimerization partner with Nrf2), facilitates the recruitment of endogenous HDAC3 to the ARE element, helps to maintain the histone hypoacetylation state in the local chromosome and hence represses ARE-dependent gene expression [77].”
BackgroundRomán-Pintos, L. M., Villegas-Rivera, G., Rodríguez-Carrizález, A. D., Miranda‐Díaz, A. G., & Cardona-Muñóz, E. G. (2016) · Journal of Diabetes Research · doi:10.1155/2016/3425617 · Cited by 252 · see citing works
“Moreover, mitochondria can also generate HO∙, H 2 O 2 , and NO∙, capable of causing deleterious effects to other proteins or the DNA [62].”
BackgroundInfluentialCoumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway
Hassanein, E. H. M., Sayed, A. M. M., Hussein, O. E., & Mahmoud, A. M. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/1675957 · Cited by 257 · see citing works
“CBP-p300 has an intrinsic acetyl transferase activity and acetylates Nrf2 and p65 [64, 65].”
BackgroundNrf2, a Guardian of Healthspan and Gatekeeper of Species Longevity
Lewis, K. N., Mele, J., Hayes, J. D., & Buffenstein, R. (2010) · Integrative and Comparative Biology · doi:10.1093/icb/icq034 · Cited by 247 · see citing works
“Moreover, NF-kB may also impede Nrf2 signaling through the induction of hypoacetylation through the recruitment of histone deacetylase 3 (HDAC) and by competitively binding to the transcription coactivator-binding protein (CBP) (Liu and Shen 2008).”
BackgroundArlt, A., Bauer, I., Schafmayer, C., Tepel, J., Müerköster, S. S., Brosch, M., Röder, C., Kalthoff, H., Hampe, J., Moyer, M. P., et al. (2009) · Oncogene · doi:10.1038/onc.2009.264 · Cited by 245 · see citing works
Redox activation of Nrf2 & NF-κB: A double end sword?
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Mechanism of the Nrf2/Keap1/ARE signaling system
Tkachev, V., Брониславовна, М. Е., & Зенков, Н. К. (2011) · Biochemistry (Moscow) · doi:10.1134/s0006297911040031 · Cited by 228 · see citing works
Nrf2: control of sensitivity to carcinogens
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“…isolated, as Nrf2 has recently been described to interact with a host of cellular signaling networks and processes including p62-mediated autophagy (Komatsu et al. 2010; Lau et al. 2010), NF-jB signaling (Liu et al. 2008), and p21/p53-based signaling (Chen et al. 2009; Wakabayashi et al. 2010b).”
BackgroundA systems biology perspective on Nrf2-mediated antioxidant response
Zhang, Q., Pi, J., Woods, C. G., & Andersen, M. E. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.08.018 · Cited by 217 · see citing works
“The promoters of many antioxidant and phase II genes also receive regulatory input from other transcription factors, such as AP-1 and NF-κB (Harada et al., 2008; Liu et al., 2008; Kimura et al., 2009), suggesting that the antioxidant response is coordinately regulated with other cellular processes such as the inflamma…”
BackgroundNrf2 and NF-κB and Their Concerted Modulation in Cancer Pathogenesis and Progression
Bellezza, I., Mierla, A. L., & Minelli, A. (2010) · Cancers · doi:10.3390/cancers2020483 · Cited by 216 · see citing works
“NF-κB p65 subunit represses the Nrf2-ARE pathway at transcriptional level [20].”
BackgroundInfluentialMolecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis
Stępkowski, T. M., & Kruszewski, M. K. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.01.033 · Cited by 212 · see citing works
“An example is the competition between NRF2 and NF-κB p65 for cAMPresponse element-binding protein (CREB) transcription cofactor binding, or the NF-κB p65-dependent recruitment of histone deacetylase, which causes local chromatin hypoacetylation inhibiting the NRF2dependent transcription of heme oxygenase 1 [42].”
BackgroundRole of Nrf2 in aging, Alzheimer’s and other neurodegenerative diseases
George, M., Tharakan, M., Culberson, J. W., Reddy, A. P., & Reddy, P. H. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101756 · Cited by 212 · see citing works
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“Accordingly, silencing of p65 by knockdown promotes Nrf2 complex formation with CBP (Liu et al., 2008).”
BackgroundOxidative Stress in Autism Spectrum Disorder—Current Progress of Mechanisms and Biomarkers
Liu, X., Jing, L., Zhang, H., Khan, N. U., Zhang, J., Tang, X., Cao, X., & Shen, L. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.813304 · Cited by 201 · see citing works
An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases
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“Of these, small Mafs (MafK, MafG, and MafF) are obligatory co-activator dimeric partners that bind to the Neh1 domain through their leucine zipper Int.”
BackgroundCrosstalk of toll-like receptors signaling and Nrf2 pathway for regulation of inflammation
Mohan, S. V., & Gupta, D. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.10.019 · Cited by 217 · see citing works
Multiple regulations of Keap1/Nrf2 system by dietary phytochemicals
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The role of transcription factor Nrf2 in skin cells metabolism
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“Moreover, NFjB recruits histone deacetylase 3 (HDAC3) causing local hypoacetylation to hamper Nrf2 signaling [66].”
BackgroundNADPH Oxidase Limits Innate Immune Responses in the Lungs in Mice
Segal, B. H., Han, W., Bushey, J. J., Joo, M., Bhatti, Z., Feminella, J., Dennis, C. G., Vethanayagam, R. R., Yull, F. E., Capitano, M. L., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009631 · Cited by 180 · see citing works
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“NF-κB p65 subunit repressed the Nrf2-ARE pathway at transcriptional level by competitive interaction with the CH1-KIX domain of CBP or local histone hypoacetylation [25].”
Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk
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The Keap1–Nrf2 Cell Defense Pathway – A Promising Therapeutic Target?
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“Further, as constitutively active NF-kB occurs in many inflammatory and tumour tissues (Liu et al, 2008), and as Nrf2 is implicated in the etiopathogenesis of many cancers and inflammation-associated conditions (Nair et al, 2007a), we elected to select these two important transcriptional regulators…”
BackgroundSaber, S., Khalil, R. M., Abdo, W. S., Nassif, D., & El-Ahwany, E. G. (2018) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2018.12.020 · Cited by 166 · see citing works
Anti‐inflammatory potential of allyl‐isothiocyanate – role of Nrf2, NF‐κB and microRNA‐155
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The small MAF transcription factors MAFF, MAFG and MAFK: Current knowledge and perspectives
Kannan, M. B., Solovieva, V., & Blank, V. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.06.012 · Cited by 161 · see citing works
Dimethyl fumarate, a two‐edged drug: Current status and future directions
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Targeting Nrf2 Signaling to Combat Chemoresistance
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“Several chemopreventive agents, such as sulforaphane, epi- gallocatechin-3-gallate, and curcumin, induce Nrf2 signaling with concomitant repression of NF-κB.14 The NF-κB p65 subunit re- presses the Nrf2-ARE pathway by preventing CREB binding pro- tein (CBP) from binding Nrf2 through competitive interaction or by promo…”
Signal pathways in the treatment of Alzheimer’s disease with traditional Chinese medicine
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MicroRNA-7 activates Nrf2 pathway by targeting Keap1 expression
Kabaria, S., Choi, D. C., Chaudhuri, A., Jain, M. R., Li, H., & Junn, E. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.09.010 · Cited by 135 · see citing works
“Interestingly, RelA reportedly inhibits Nrf2 pathway either by selectively depriving CREB binding protein (CBP) from Nrf2, which results in inactivation of Nrf2, or directly interacting with Keap1, which leads to nuclear localization of Keap1 and subsequent inhibition of Nrf2 activity [32,33].”
Turpaev, K. T. (2013) · Biochemistry (Moscow) · doi:10.1134/s0006297913020016 · Cited by 135 · see citing works
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The Nrf2 pathway in the progression of renal disease
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“Experiments provided the evidence that the NF-kB p65 subunit and Nrf2 both bind to the same domain of CBP, a well-established coactivator of Nrf2, and that p65 after phosphorylation at Ser276, through a competitive mechanism, suppresses transcription of AREdependent genes by depriving CBP from Nrf2 [26].”
BackgroundNrf2: An all-rounder in depression
Zuo, C., Cao, H., Song, Y., Gu, Z., Huang, Y., Yang, Y., Miao, J., Zhu, L., Chen, J., Jiang, Y., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102522 · Cited by 138 · see citing works
Mechanisms of action of isothiocyanates in cancer chemoprevention: an update
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“When p65 binds CBP first, it promotes recruitment of HDAC3 to AREs, resulting in inactivation of Nrf2 [32].”
BackgroundMichalak, K. P., & Michalak, A. Z. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1558263 · Cited by 132 · see citing works
“This inhibitory effect of NF-k B occurs by competing with the CH1-KIX domain of CBP while also promoting the phosphorylation of p65 at Ser276, which in turn prevents CBP from binding to Nrf2 (458, 459).”
Jastrząb, A., Gęgotek, A., & Skrzydlewska, E. (2019) · Cells · doi:10.3390/cells8080827 · Cited by 121 · see citing works
“Aldehyde was measured by GC/MSMS (Agilent Technologies, Palo Alto, CA, USA), as the O-PFBoxime-TMS derivative, using a modified method of Liu and co-authors [39].”
BackgroundMethodProtective Role of Nrf2 in Renal Disease
Guerrero‐Hue, M., Rayego‐Mateos, S., Vázquez‐Carballo, C., Palomino‐Antolín, A., García‐Caballero, C., Opazo-Ríos, L., Morgado‐Pascual, J. L., Herencia, C., Mas, S., Ortíz, A., et al. (2020) · Antioxidants · doi:10.3390/antiox10010039 · Cited by 121 · see citing works
“CBP, which is required by both transcription factors, thus reducing the expression of NFκB-modulated genes [101].”
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“In addition, CBP interacts with phosphorylated p65 at Ser276, thus in the case with the overexpression of p65, it inhibits the availability of CBP for Nrf2 connection [25].”
BackgroundInduction of NRF2‐mediated gene expression by dietary phytochemical flavones apigenin and luteolin
Paredes‐Gonzalez, X., Fuentes, F., Jeffery, S., Saw, C. L. L., Shu, L., Su, Z., & Kong, A. T. (2015) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.1956 · Cited by 118 · see citing works
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“Nrf2 and NF-κB cross each other at various interfaces affecting each other’s activities [51].”
BackgroundAging: Molecular Pathways and Implications on the Cardiovascular System
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“Thus, in the increase in ROS production, Nrf-2 begins to have its activity inhibited by the crosstalk with Nf-kB, which is responsible for increasing TNF-α levels, generating a vicious cycle [77].”
BackgroundThe Role of the Nrf2 Signaling in Obesity and Insulin Resistance
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Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression
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- Authors
- Liu, G.-H., Qu, J., & Shen, X.
- Affiliations
- Chinese Academy of Sciences (CN)
- Corresponding author
- Shen, Xun
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 1783
- Issue
- 5
- Pages
- 713-727
- ISSN
- 0167-4889 (ISSN-L)
- OpenAlex
- W2113024198
- Cited by
- 697
- References
- 77
- Citations by year
- 2026: 54 · 2025: 45 · 2024: 51 · 2023: 47 · 2022: 68 · 2021: 51 · 2020: 59 · 2019: 59 · 2018: 47 · 2017: 38 · 2016: 32 · 2015: 33 · 2014: 15 · 2013: 28 · 2012: 13
- FWCI
- 7.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1904 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (30330250, 30570462)
- Shanghai Municipal Education Commission (E-04010)
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- NF-κB p65, Nrf2, antioxidant response element, CBP, HDAC3, MafK, heme oxygenase-1, transcriptional repression, histone deacetylation, histone hypoacetylation, PKA phosphorylation, corepressor recruitment, anti-inflammatory signaling
- MeSH terms
- Histone Deacetylase 3, Antioxidants, Cell Line, Gene Expression Regulation, Histone Deacetylases, Humans, Transcription, Genetic, Trans-Activators, NF-kappa B, Response Elements, CREB-Binding Protein, MafK Transcription Factor, NF-E2-Related Factor 2, Transcription Factor RelA
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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