CoChat
Sign Up
Cited by 8Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressGenetics, Aging, and Longevity in Model Organisms

The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.

Functional analysis of bipartite NRF2 activators that overcome feedback regulation for age-related chronic diseases

Open access
Hushpulian, Dmitry M., Kaidery, Navneet Ammal, Soni, Priyanka, Poloznikov, Andrey A., Zakhariants, Arpenik A., Razumovskaya, Alexandra V., Silkina, Mariia O., Tishkov, Vladimir I., Kazakov, Eliot H., Brown, Abraham M., Gaisina, Irina N., Ahn, Young-Hoon, Kazakov, Sergey V., Krucher, Nancy, Sharma, Sudarshana M., Paul, Bindu D., Gazaryan, Irina G., Nikulin, Sergey V., Thomas, Bobby·2025·Redox Biology
DOI 10.1016/j.redox.2025.103794PMC PMC12356038

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Activating Nrf2 with small molecules is a promising strategy for countering aging, oxidative stress, inflammation, and various disorders, including neurodegeneration. The primary regulator of Nrf2 protein stability is Keap1, a redox sensor protein and an adapter in the Cullin III ubiquitin ligase complex, which labels Nrf2 for proteasomal degradation. The known Nrf2 activators either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered the most suitable for continuous administration, as non-specific chemical modifiers of Keap1 thiols also modify active thiols on other proteins, thus causing side effects. However, when transitioning from homogeneous to cell-based assays, genuine displacement activators show a significant loss in potency by several orders of magnitude. As we demonstrate here, this offset is due to the presence of high micromolar concentrations of Keap1 in both the cell lines and brain tissue. A potential solution could involve targeted delivery of an alkylating agent to Keap1 to achieve the desired specificity. Transcriptomic analysis of a cell-permeable Nrf2 peptide bearing an alkylating fumarate moiety indicates selective activation of the Nrf2 genetic program, confirming the high specificity of this approach. The Nrf2-triggered genetic program has a feedback regulation mechanism through the activation of Bach1, an Nrf2 transcriptional repressor, which is elevated in age-related neurodegeneration. Thus, a benign bipartite Nrf2 activator with Bach1 inhibition properties is needed for maximal benefits. The recently developed heterocyclic carboxamide, HPPE, shows overlap with the Nrf2 pathway activated by the fumarate-linked Nrf2 peptide and with zinc and tin protoporphyrins, which are recognized inhibitors of Bach1. Therefore, HPPE presents a promising and unique combination of the two desired activities that could be further optimized to treat age-related neurodegeneration. Highlights: The decrease in potency for reversible displacement activators of Nrf2 in biological assays is attributed to high micromolar concentrations of Keap1 and competition with endogenous Keap1 client proteins.Nrf2 activators specific for Keap1 should combine a displacement scaffold with a substitution that undergoes intracellular conversion into active pro-oxidant or alkylating species.Cell-permeable fumarate-linked Nrf2 peptide solely activates the Nrf2 antioxidant genetic program, as demonstrated by transcriptomic analysis.HPPE, a small bipartite molecule, exhibits properties of both Nrf2 activation and Bach1 inhibition, to bypass feedback regulation by targeting both Keap1 and Bach1.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.redox.2025.103794

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 85

  1. Harder, 2015, Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention, Biochem. Soc. Trans., 43, 680, 10.1042/BST20150020 · DOI
  2. Lee, 2007, 'An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance', J. Biol. Chem., 282, 36412, 10.1074/jbc.M706517200 · DOI
  3. Jyrkkanen, 2011, Novel insights into the regulation of antioxidant-response-element-mediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by Nrf2, Biochem. J., 440, 167, 10.1042/BJ20110526 · DOI
  4. Kopacz, 2020, Keap1 governs ageing-induced protein aggregation in endothelial cells, Redox Biol., 34, 10.1016/j.redox.2020.101572 · DOI
  5. Heurtaux, 2022, Normal and pathological NRF2 signalling in the central nervous system, Antioxidants, 11, 10.3390/antiox11081426 · DOI
  6. Xiao, 2024, Regulation of Keap1-Nrf2 signaling in health and diseases, Mol. Biol. Rep., 51, 809, 10.1007/s11033-024-09771-4 · DOI
  7. Kubben, 2016, Repression of the antioxidant NRF2 pathway in premature aging, Cell, 165, 1361, 10.1016/j.cell.2016.05.017 · DOI · Paper page
  8. Dinkova-Kostova, 2023, Advances and challenges in therapeutic targeting of NRF2, Trends Pharmacol. Sci., 44, 137, 10.1016/j.tips.2022.12.003 · DOI
  9. Ahuja, 2021, Bach1 derepression is neuroprotective in a mouse model of parkinson's disease, Proc. Natl. Acad. Sci. U. S. A., 118, 10.1073/pnas.2111643118 · DOI
  10. Smirnova, 2011, 'Development of Neh2-luciferase reporter and its application for high throughput screening and real-time monitoring of Nrf2 activators', Chem Biol, 18, 752, 10.1016/j.chembiol.2011.03.013 · DOI
  11. Schmittgen, 2008, Analyzing real-time PCR data by the comparative C(T) method, Nat. Protoc., 3, 1101, 10.1038/nprot.2008.73 · DOI · Paper page
  12. Parvez, 2015, 'Substoichiometric hydroxynonenylation of a single protein recapitulates whole-cell-stimulated antioxidant response', J. Am. Chem. Soc., 137, 10, 10.1021/ja5084249 · DOI
  13. Lau, 2013, The predicted molecular weight of Nrf2: it is what it is not, Antioxid Redox Signal, 18, 91, 10.1089/ars.2012.4754 · DOI
  14. Ewels, 2016, 'MultiQC: summarize analysis results for multiple tools and samples in a single report', Bioinformatics, 32, 3047, 10.1093/bioinformatics/btw354 · DOI · Paper page
  15. Chen, 2018, 'fastp: an ultra-fast all-in-one FASTQ preprocessor', Bioinformatics, 34, i884, 10.1093/bioinformatics/bty560 · DOI · Paper page
  16. Dobin, 2013, STAR: ultrafast universal RNA-Seq aligner, Bioinformatics, 29, 15, 10.1093/bioinformatics/bts635 · DOI · Paper page
  17. Frankish, 2019, 'GENCODE reference annotation for the human and mouse genomes', Nucleic Acids Res., 47, D766, 10.1093/nar/gky955 · DOI
  18. Liao, 2013, The subread aligner: fast, accurate and scalable read mapping by seed-and-vote, Nucleic Acids Res., 41, 10.1093/nar/gkt214 · DOI · Paper page
  19. Liao, 2014, featureCounts: an efficient general purpose program for assigning sequence reads to genomic features, Bioinformatics, 30, 923, 10.1093/bioinformatics/btt656 · DOI · Paper page
  20. Zhang, 2020, ComBat-seq: batch effect adjustment for RNA-Seq count data, NAR Genom Bioinform, 2
  21. Gu, 2022, Make interactive complex heatmaps in R, Bioinformatics, 38, 1460, 10.1093/bioinformatics/btab806 · DOI
  22. Chen, 2013, Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool, BMC Bioinf., 14, 128, 10.1186/1471-2105-14-128 · DOI · Paper page
  23. Langfelder, 2008, WGCNA: an R package for weighted correlation network analysis, BMC Bioinf., 9, 559, 10.1186/1471-2105-9-559 · DOI · Paper page
  24. Ashburner, 2000, 'Gene ontology: tool for the unification of biology. The Gene Ontology Consortium', Nat. Genet., 25, 25, 10.1038/75556 · DOI · Paper page
  25. Thomas, 2022, PANTHER: making genome-scale phylogenetics accessible to all, Protein Sci., 31, 8, 10.1002/pro.4218 · DOI · Paper page
  26. Lu, 2016, An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis, Sci. Rep., 6
  27. Plusa, 2022, Management of patients with chronic obstructive pulmonary disease (COPD) during COVID-19, Pol Merkur Lekarski, 50, 262
  28. Fukutomi, 2014, 'Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1', Mol. Cell Biol., 34, 832, 10.1128/MCB.01191-13 · DOI
  29. Hushpulian, 2021, Challenges and limitations of targeting the Keap1-Nrf2 pathway for neurotherapeutics: Bach1 De-Repression to the rescue, Front. Aging Neurosci., 13, 10.3389/fnagi.2021.673205 · DOI
  30. Iso, 2016, Absolute amounts and status of the Nrf2-Keap1-Cul3 complex within cells, Mol. Cell Biol., 36, 3100, 10.1128/MCB.00389-16 · DOI
  31. Hu, 2013, Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction, Bioorg. Med. Chem. Lett., 23, 3039, 10.1016/j.bmcl.2013.03.013 · DOI
  32. Winkel, 2015, Characterization of RA839, a noncovalent small molecule binder to Keap1 and selective activator of Nrf2 signaling, J. Biol. Chem., 290, 28446, 10.1074/jbc.M115.678136 · DOI
  33. Sun, 2022, 'Design, synthesis and evaluation of novel small molecules acting as Keap1-Nrf2 protein-protein interaction inhibitors', J Enzyme Inhib Med Chem, 37, 2575, 10.1080/14756366.2022.2124408 · DOI
  34. Gaisina, 2021, Identification of a potent Nrf2 displacement activator among aspirin-containing prodrugs, Neurochem. Int., 149, 10.1016/j.neuint.2021.105148 · DOI
  35. Jagannathan, 2016, Oxidative stress under ambient and physiological oxygen tension in tissue culture, Curr Pharmacol Rep, 2, 64, 10.1007/s40495-016-0050-5 · DOI
  36. Edres, 2021, The potential neuroprotective effect of allicin and melatonin in acrylamide-induced brain damage in rats, Environ. Sci. Pollut. Res. Int., 28, 58768, 10.1007/s11356-021-14800-x · DOI
  37. Grinberg, 2011, Brainstem: neglected locus in neurodegenerative diseases, Front. Neurol., 2, 42, 10.3389/fneur.2011.00042 · DOI
  38. Dutt, 2021, Brainstem substructures and cognition in prodromal alzheimer's disease, Brain Imaging Behav, 15, 2572, 10.1007/s11682-021-00459-y · DOI
  39. Vijayan, 2020, Brainstem ventilatory dysfunction: a plausible mechanism for dyspnea in parkinson's disease?, Mov. Disord., 35, 379, 10.1002/mds.27932 · DOI
  40. Majkutewicz, 2022, Dimethyl fumarate: a review of preclinical efficacy in models of neurodegenerative diseases, Eur. J. Pharmacol., 926, 10.1016/j.ejphar.2022.175025 · DOI
  41. Pant, 2024, 'Regulation of immunomodulatory networks by Nrf2-activation in immune cells: redox control and therapeutic potential in inflammatory diseases', Redox Biol., 70, 10.1016/j.redox.2024.103077 · DOI
  42. Jung, 2012, '8-(Tosylamino)quinoline inhibits macrophage-mediated inflammation by suppressing NF-kappaB signaling', Acta Pharmacol. Sin., 33, 1037, 10.1038/aps.2012.52 · DOI
  43. Zhuang, 2014, Rapid identification of Keap1-Nrf2 small-molecule inhibitors through structure-based virtual screening and hit-based substructure search, J. Med. Chem., 57, 1121, 10.1021/jm4017174 · DOI
  44. Lu, 2020, Discovery of 2-oxy-2-phenylacetic acid substituted naphthalene sulfonamide derivatives as potent KEAP1-NRF2 protein-protein interaction inhibitors for inflammatory conditions, Eur. J. Med. Chem., 207, 10.1016/j.ejmech.2020.112734 · DOI
  45. Jiang, 2018, Identification of a novel small-molecule Keap1-Nrf2 PPI inhibitor with cytoprotective effects on LPS-Induced cardiomyopathy, J Enzyme Inhib Med Chem, 33, 833, 10.1080/14756366.2018.1461856 · DOI
  46. Hancock, 2012, 'Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction', Free Radic. Biol. Med., 52, 444, 10.1016/j.freeradbiomed.2011.10.486 · DOI
  47. Steel, 2012, 'Anti-inflammatory Effect of a Cell-Penetrating Peptide Targeting the Nrf2/Keap1 Interaction', ACS Med. Chem. Lett., 3, 407, 10.1021/ml300041g · DOI
  48. Carrow, 2024, Inhibiting the Keap1/Nrf2 protein-protein interaction with protein-like polymers, Adv Mater, 36, 10.1002/adma.202311467 · DOI
  49. Mesfin, 2025, 'Protein-Like Polymers Targeting Keap1/Nrf2 as Therapeutics for Myocardial Infarction', Adv Mater, 10.1002/adma.202417885 · DOI
  50. Tu, 2015, 'Cell-Permeable Peptide Targeting the Nrf2-Keap1 Interaction: a Potential Novel Therapy for Global Cerebral Ischemia', J. Neurosci., 35, 14727, 10.1523/JNEUROSCI.1304-15.2015 · DOI
  51. Ahuja, 2016, Distinct Nrf2 signaling mechanisms of fumaric acid esters and their role in neuroprotection against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced experimental parkinson's-like disease, J. Neurosci., 36, 6332, 10.1523/JNEUROSCI.0426-16.2016 · DOI
  52. Xiao, 2021, Long non-coding RNA LUCAT1 inhibits myocardial oxidative stress and apoptosis after myocardial infarction via targeting microRNA-181a-5p, Bioengineered, 12, 4546, 10.1080/21655979.2021.1966351 · DOI
  53. Shu, 2018, DnaJ homolog subfamily A member1 (DnaJ1) is a newly discovered anti-apoptotic protein regulated by azadirachtin in Sf9 cells, BMC Genom., 19, 413, 10.1186/s12864-018-4801-z · DOI
  54. Simoes-Correia, 2014, DNAJB4 molecular chaperone distinguishes WT from mutant E-cadherin, determining their fate in vitro and in vivo, Hum. Mol. Genet., 23, 2094, 10.1093/hmg/ddt602 · DOI
  55. Lei, 2011, A novel neuron-enriched protein SDIM1 is Down regulated in Alzheimer's brains and attenuates cell death induced by DNAJB4 over-expression in neuro-progenitor cells, Mol. Neurodegener., 6, 9, 10.1186/1750-1326-6-9 · DOI
  56. Feng, 2018, 'Proteasome subunit-alpha type-6 protein is post-transcriptionally repressed by the microRNA-4490 in diabetic nephropathy', Biosci. Rep., 38, 10.1042/BSR20180815 · DOI
  57. Nguyen, 2024, Molecular mechanisms implicated in protein changes in the alzheimer's disease human hippocampus, Mech. Ageing Dev., 219, 10.1016/j.mad.2024.111930 · DOI
  58. Xie, 2024, Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke, J. Transl. Med., 22, 248, 10.1186/s12967-024-04993-3 · DOI
  59. Singleton, 2014, OGFOD1 catalyzes prolyl hydroxylation of RPS23 and is involved in translation control and stress granule formation, Proc. Natl. Acad. Sci. U. S. A., 111, 4031, 10.1073/pnas.1314482111 · DOI
  60. Chen, 2000, The gamma-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) promotes GABAA receptor clustering and modulates the channel kinetics, Proc. Natl. Acad. Sci. U. S. A., 97, 11557, 10.1073/pnas.190133497 · DOI
  61. Du, 2022, 'Loss of GABARAPL1 confers ferroptosis resistance to cancer stem-like cells in hepatocellular carcinoma', Mol. Oncol., 16, 3703, 10.1002/1878-0261.13305 · DOI
  62. Puigdellivol, 2021, The microglial P2Y(6) receptor mediates neuronal loss and memory deficits in neurodegeneration, Cell Rep., 37, 10.1016/j.celrep.2021.110148 · DOI
  63. Anwar, 2020, Microglia purinoceptor P2Y6: an emerging therapeutic target in CNS diseases, Cells, 9, 10.3390/cells9071595 · DOI
  64. Le Vasseur, 2019, Pannexin 2 localizes at ER-Mitochondria contact sites, Cancers (Basel), 11, 10.3390/cancers11030343 · DOI
  65. Liao, 2020, Identification of pannexin 2 as a novel marker correlating with ferroptosis and malignant phenotypes of prostate cancer cells, OncoTargets Ther., 13, 4411, 10.2147/OTT.S249752 · DOI
  66. Park, 2024, Identification of novel NRF2-dependent genes as regulators of lead and arsenic toxicity in neural progenitor cells, J Hazard Mater, 463, 10.1016/j.jhazmat.2023.132906 · DOI
  67. Chen, 2011, 'A novel binding protein of single immunoglobulin IL-1 receptor-related molecule: paralemmin-3', Biochem. Biophys. Res. Commun., 404, 1029, 10.1016/j.bbrc.2010.12.104 · DOI
  68. Buccheri, 1986, MACC (methotrexate, doxorubicin, cyclophosphamide and lomustine) versus cis-platinum and etoposide in the treatment of advanced non-small cell lung cancer, Chemioterapia, 5, 53
  69. Patel, 2016, 'Importance of Hepatic Transporters in Clinical Disposition of Drugs and Their Metabolites', J. Clin. Pharmacol., 56, S23
  70. Alva, 2022, Culture of cancer cells at physiological oxygen levels affects gene expression in a cell-type specific manner, Biomolecules, 12, 10.3390/biom12111684 · DOI
  71. Jyothidasan, 2022, 'Transgenic Expression of Nrf2 Induces a Pro-Reductive Stress and Adaptive Cardiac Remodeling in the Mouse', Genes, 13, 10.3390/genes13091514 · DOI
  72. Gu, 2024, Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance, Proc. Natl. Acad. Sci. U. S. A., 121, 10.1073/pnas.2320934121 · DOI
  73. Zhang, 2019, 'Silencing Bach1 alters aging-related changes in the expression of Nrf2-regulated genes in primary human bronchial epithelial cells', Arch. Biochem. Biophys., 672, 10.1016/j.abb.2019.108074 · DOI
  74. Ogawa, 2001, 'Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1', EMBO J., 20, 2835, 10.1093/emboj/20.11.2835 · DOI
  75. Hou, 2008, 'Zinc mesoporphyrin induces rapid and marked degradation of the transcription factor Bach1 and up-regulates HO-1', Biochim. Biophys. Acta, 1779, 195, 10.1016/j.bbagrm.2008.01.006 · DOI
  76. Abate, 2007, The role of Bach1 in the induction of heme oxygenase by tin mesoporphyrin, Biochem. Biophys. Res. Commun., 354, 757, 10.1016/j.bbrc.2007.01.050 · DOI
  77. Attucks, 2014, 'Induction of heme oxygenase I (HMOX1) by HPP-4382: a novel modulator of Bach1 activity', PLoS One, 9, 10.1371/journal.pone.0101044 · DOI
  78. Freeman, 2024, HPPE activates NRF2 signaling by liberating heavy metal stores, Chembiochem
  79. Zinovkin, 2022, Does Nrf2 play a role of a master regulator of mammalian aging?, Biochemistry (Mosc), 87, 1465, 10.1134/S0006297922120045 · DOI
  80. Diaz, 2024, Age-dependent changes in Nrf2/Keap1 and target antioxidant protein expression correlate to lipoxidative adducts, and are modulated by dietary N-3 LCPUFA in the hippocampus of mice, Antioxidants, 13, 10.3390/antiox13020206 · DOI
  81. Davinelli, 2014, Altered expression pattern of Nrf2/HO-1 axis during accelerated-senescence in HIV-1 transgenic rat, Biogerontology, 15, 449, 10.1007/s10522-014-9511-6 · DOI
  82. Zhang, 2012, Nrf2-regulated phase II enzymes are induced by chronic ambient nanoparticle exposure in young mice with age-related impairments, Free Radic. Biol. Med., 52, 2038, 10.1016/j.freeradbiomed.2012.02.042 · DOI
  83. Dias, 2013, The role of oxidative stress in parkinson's disease, J. Parkinsons Dis., 3, 461, 10.3233/JPD-130230 · DOI · Paper page
  84. Aleksander, 2023, ‘The Gene Ontology knowledgebase in 2023’, Genetics, 224
  85. Khristichenko, 2019, Quantitative analysis of cell-based luciferase fusion reporters, Mosc. Univ. Chem. Bull., 74, 180, 10.3103/S0027131419040047 · DOI

Metadata

Authors
Hushpulian, D. M., Kaidery, N. A., Soni, P., Poloznikov, A. A., Zakhariants, A. A., Razumovskaya, A. V., Silkina, M. O., Tishkov, V. I., Kazakov, E. H., Brown, A. M., Gaisina, I. N., Ahn, Y.-H., Kazakov, S. V., Krucher, N., Sharma, S. M., Paul, B. D., Gazaryan, I. G., Nikulin, S. V., & Thomas, B.
Affiliations
  • Russian Academy of Sciences (RU)
  • Medical University of South Carolina (US)
  • National Research University Higher School of Economics (RU)
  • Lomonosov Moscow State University (RU)
  • New York Medical College (US)
  • University of Illinois Chicago (US)
  • Drexel University (US)
  • Pace University (US)
  • Johns Hopkins University (US)
Corresponding author
Thomas, Bobby
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2025-10
Volume
86
Pages
103794
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2025.103794
PMC
PMC12356038
OpenAlex
W4412739214
Cited by
8
References
5
Citations by year
2026: 7 · 2025: 1
FWCI
2.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • Touro Scholar (Touro College) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Research University Higher School of Economics (P01CA203653)
  • US Department of Defense (HT94252310443)
  • Allen Foundation (19PABH134580006, 1R21AG073684, R01AG071512)
  • Johns Hopkins University
  • National Institutes of Health (R01NS133688, R01NS101967, R01AG077396)
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 › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
Nrf2 activation, Keap1, feedback regulation, BACH1, age-related neurodegeneration, oxidative stress, inflammation, alkylating agents, protoporphyrin IX, targeted delivery

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 ›

Are you an author, or do you see a problem with this page? Request a review