Affinage

KEAP1

Kelch-like ECH-associated protein 1 · UniProt Q14145

Length
624 aa
Mass
69.7 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KEAP1 is the substrate-recognition adaptor of a CUL3-RBX1 cullin-RING E3 ubiquitin ligase that constitutively ubiquitinates the transcription factor NRF2, targeting it for proteasomal degradation and thereby gating the cytoprotective antioxidant response under basal conditions (PMID:15706085, PMID:15519281, PMID:17145701, PMID:11909699). Structurally, KEAP1 assembles as a homodimer with CUL3, and its Kelch domain captures NRF2 through a two-site (DLG and ETGE motif) interaction that presents NRF2 for ubiquitination (PMID:26057936). KEAP1 acts as a cysteine-based stress sensor: oxidative and electrophilic signals modify reactive cysteine residues—principally Cys151 in the BTB domain and Cys273/Cys288 in the intervening domain—producing a conformational change that disrupts the KEAP1-CUL3 interaction and impairs NRF2 ubiquitination, allowing NRF2 to accumulate and translocate to the nucleus (PMID:19560482). Diverse modifiers converge on these cysteines, including the macrophage metabolite itaconate (PMID:29590092), methylglyoxal-derived methylimidazole crosslinks generated upon PGK1 inhibition (PMID:30323285), the electrophile curcumin (PMID:31972171), and hydrogen sulfide via S-sulfhydration (PMID:38359744), establishing KEAP1 as an integrator of metabolic and redox stress. Beyond NRF2, KEAP1 ubiquitinates additional substrates including PGAM5 in an AMPK-associated complex to protect against necroptosis (PMID:29579593) and, downstream of PINK1, the ER-phagy receptor Rtnl1 to direct selective ER clearance (PMID:37633267). KEAP1 activity is further tuned by competitive binding partners—phosphorylated p62 whose KEAP1 affinity is enhanced by mTORC1 and NBR1-driven droplet formation (PMID:24011591, PMID:31916398), GULP1 (PMID:32817372), and DDRGK1 (PMID:36965071)—by chaperone-mediated autophagy of KEAP1 itself (PMID:35535673), and by PRMT5-mediated methylation (PMID:37380368). Loss of KEAP1 drives constitutive NRF2 signaling with consequences for lysosomal biogenesis (PMID:37216554) and for the response to targeted kinase inhibitors in lung cancer (PMID:28145866).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2002 High

    Established that the human KEAP1 homolog physically sequesters NRF2 in the cytoplasm and that this interaction is redox-sensitive, defining the core regulatory relationship.

    Evidence Reciprocal co-IP, immunofluorescence, and GCLC reporter assays with redox perturbation in cells

    PMID:11909699

    Open questions at the time
    • Did not define the enzymatic mechanism by which KEAP1 controls NRF2 levels
    • No molecular identification of the redox-sensing residues
  2. 2005 High

    Resolved how KEAP1 controls NRF2 abundance by showing it is the substrate adaptor of a CUL3 E3 ligase that ubiquitinates NRF2 for degradation, with release under stress.

    Evidence In vitro ubiquitination assays, proteasome inhibition, and keap1-knockout mice

    PMID:15519281 PMID:15706085 PMID:17145701

    Open questions at the time
    • Did not pinpoint which cysteines act as the stress sensor
    • Structural basis of NRF2 presentation unresolved
  3. 2009 High

    Identified the functionally distinct sensor cysteines (Cys151 vs Cys273/Cys288) and showed Cys151 modification dissociates KEAP1 from CUL3, providing the molecular basis of stress sensing.

    Evidence Site-directed mutagenesis with functional readout supported by proteomic analysis

    PMID:19560482

    Open questions at the time
    • Did not establish whether different inducers preferentially target different cysteines
    • Conformational changes not directly visualized
  4. 2009 Medium

    Proposed an on/off switching model coupling KEAP1 cysteine modification with kinase-mediated NRF2 phosphorylation (PKC, GSK3β/Fyn) to control NRF2 nuclear import and export.

    Evidence Kinase phosphorylation assays, mutagenesis, nuclear fractionation, and co-IP

    PMID:19666107

    Open questions at the time
    • Some cascade steps inferred from indirect evidence
    • Relative contribution of cysteine versus phosphorylation arms not quantified
  5. 2014 Medium

    Used live-cell FRET-FLIM to support a cyclic sequential attachment-and-regeneration model in which KEAP1 continuously turns over NRF2 until cysteine modification halts the cycle.

    Evidence FRET and multiphoton FLIM imaging of KEAP1-NRF2 in single living cells

    PMID:24681086

    Open questions at the time
    • Single advanced-imaging approach from one lab
    • Does not directly link dynamics to ubiquitin transfer kinetics
  6. 2015 High

    Provided the 3D structural framework, showing KEAP1 homodimerizes with CUL3 and binds NRF2 via two-site DLG/ETGE recognition, rationalizing how cysteine modification disrupts substrate presentation.

    Evidence X-ray crystallography and protein-protein interaction studies

    PMID:26057936

    Open questions at the time
    • Static structures do not capture the inducer-triggered conformational transition directly
    • Structures of modified-cysteine states not defined
  7. 2013 High

    Connected selective autophagy to NRF2 activation by showing mTORC1-phosphorylated p62 competitively sequesters KEAP1, defining a non-canonical activation route.

    Evidence Co-IP, phosphorylation mapping, mTORC1-dependent and genetic deletion/rescue assays

    PMID:24011591

    Open questions at the time
    • Did not establish in vivo physiological triggers of this branch
    • Stoichiometry of competition with NRF2 unresolved
  8. 2018 High

    Demonstrated that endogenous and metabolic electrophiles directly modify KEAP1 cysteines—itaconate alkylation and methylglyoxal-derived crosslinking—linking immunometabolism and glycolysis to NRF2 activation.

    Evidence Mass spectrometry covalent mapping, crosslinking assays, genetic KO macrophages and inhibitor studies with NRF2 reporters

    PMID:29590092 PMID:30323285

    Open questions at the time
    • Did not resolve which physiological conditions dominate in vivo
    • Quantitative thresholds for activation per modification unclear
  9. 2018 Medium

    Expanded the KEAP1 substrate repertoire beyond NRF2 by showing AMPK-associated KEAP1 ubiquitinates PGAM5 to protect against necroptosis.

    Evidence Co-IP, ubiquitination assays, AMPK genetic constructs, and Langendorff heart perfusion

    PMID:29579593

    Open questions at the time
    • Direct versus complex-mediated ubiquitin transfer to PGAM5 not fully separated
    • Single lab study
  10. 2020 Medium

    Identified competitive cytoplasmic partners (GULP1, NBR1) that modulate KEAP1-NRF2 sequestration, with disease relevance to chemoresistance.

    Evidence Co-IP, siRNA/KO, live-cell droplet imaging, NRF2 translocation and xenograft assays

    PMID:31916398 PMID:32817372

    Open questions at the time
    • Reciprocal validation of some interactions limited
    • Generality across cell types untested
  11. 2020 High

    Confirmed curcumin as a Cys151-directed electrophilic modifier that stabilizes NRF2 by inhibiting KEAP1-mediated ubiquitination.

    Evidence MS, C151S mutagenesis, ubiquitination and reporter assays

    PMID:31972171

    Open questions at the time
    • Selectivity for Cys151 over other cysteines not exhaustively mapped
  12. 2022 Medium

    Revealed feedback control of KEAP1 abundance itself, showing chaperone-mediated autophagy degrades KEAP1 to amplify NRF2 signaling in a feed-forward loop.

    Evidence CMA activation/inhibition, lysosomal fractionation, siRNA, and NRF2 translocation imaging

    PMID:35535673

    Open questions at the time
    • Recognition motif on KEAP1 for CMA not defined
    • Physiological triggers of CMA-mediated KEAP1 turnover unclear
  13. 2022 Medium

    Demonstrated KEAP1 can be repurposed as an E3 ligase for targeted protein degradation, while revealing a narrow target scope and propensity for self-degradation.

    Evidence Bivalent degrader synthesis and cell-based degradation assays against BET proteins and FAK

    PMID:36070758

    Open questions at the time
    • Structural basis of narrow target scope unresolved
    • Determinants of KEAP1 self-degradation undefined
  14. 2023 High

    Placed KEAP1 in organelle quality control by showing PINK1-directed, KEAP1-CUL3-dependent ubiquitylation of Rtnl1 drives ER-phagy, balanced against Parkin-mediated mitophagy.

    Evidence Drosophila genetic epistasis, ubiquitylation assays, and confocal localization imaging

    PMID:37633267

    Open questions at the time
    • Mechanism of PINK1 control over KEAP1 localization not fully defined
    • Conservation of Rtnl1 substrate role in mammals untested here
  15. 2023 Medium

    Identified additional KEAP1 regulators—DDRGK1 competitive binding and PRMT5 methylation—that tune NRF2 ubiquitination, ferroptosis resistance, and iron metabolism.

    Evidence Co-IP, ubiquitination/methylation assays, CRISPR KO, and ferroptosis/xenograft assays

    PMID:36965071 PMID:37380368

    Open questions at the time
    • Methylation site(s) on KEAP1 not pinpointed
    • Interplay with cysteine sensing not addressed
  16. 2023 Medium

    Extended KEAP1-NRF2 function beyond antioxidant defense by showing KEAP1 loss activates TFEB/TFE3-dependent lysosomal biogenesis in a conserved manner.

    Evidence Genetic KEAP1 knockout in zebrafish and mammalian cells with transcriptomics and NRF2 rescue

    PMID:37216554

    Open questions at the time
    • Direct molecular link between NRF2 and TFEB/TFE3 not defined
    • Whether KEAP1 acts on lysosomal regulators directly unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many independent inputs—distinct cysteine modifications, competitive binders, KEAP1 turnover, and methylation—are integrated to set NRF2 output thresholds, and how non-NRF2 substrate selection is determined, remains unresolved.
  • No unified quantitative model integrating the diverse KEAP1 modifications
  • Determinants of substrate choice between NRF2, PGAM5, and Rtnl1 unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140299 molecular sensor activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0016874 ligase activity 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
CUL3DDRGK1GULP1NBR1NFE2L2PGAM5PRMT5SQSTM1
Complex memberships
KEAP1-CUL3-RBX1 E3 ubiquitin ligaseKEAP1-PGAM5-AMPK complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 KIAA0132 (human Keap1 homolog) physically interacts with Nrf2 and sequesters it in the cytoplasm; indomethacin treatment disrupts this interaction in a redox-dependent manner, allowing Nrf2 nuclear translocation and gamma-glutamylcysteine synthetase expression. Over-expression of KIAA0132 inhibited GCLC reporter activity, and N-acetylcysteine blocked both release of Nrf2 and nuclear translocation, demonstrating the redox-sensitive nature of the Nrf2–Keap1 complex. Immunoprecipitation (co-IP), indirect immunofluorescence, reporter gene assay, overexpression/dominant-negative experiments Free radical biology & medicine High 11909699
2005 Keap1 functions as a substrate-specific adaptor of a Cul3-based E3 ubiquitin ligase, directly mediating ubiquitination and proteasomal degradation of Nrf2 under basal conditions. Under oxidative/electrophilic stress, Nrf2 is released from Keap1 and escapes degradation. Biochemical assays for ubiquitination, proteasome inhibition experiments, genetic studies in keap1-knockout mice Antioxidants & redox signaling High 15519281 15706085 17145701
2009 Keap1 contains at least two distinct functionally important cysteine motifs: Cys151 in the BTB domain and Cys273/Cys288 in the intervening domain. Adduction or oxidation at Cys151 produces a conformational change in Keap1 that dissociates it from Cul3, thereby inhibiting Nrf2 ubiquitylation. Site-directed mutagenesis and proteomic analysis support this model. Site-directed mutagenesis, proteomic analysis, biochemical functional assays Toxicology and applied pharmacology High 19560482
2009 Nrf2 activity is regulated through a 'switching on and off' mechanism: Cys151 oxidation/modification of Keap1 and/or PKC-mediated phosphorylation of Nrf2 Ser40 releases Nrf2 from Keap1. Subsequently, GSK3β phosphorylates Fyn kinase, which then phosphorylates Nrf2 Tyr568, causing nuclear export of Nrf2, re-binding to Keap1, and proteasomal degradation. Kinase phosphorylation assays, mutagenesis, nuclear fractionation, co-IP Free radical biology & medicine Medium 19666107
2013 mTORC1-dependent phosphorylation of the autophagy adaptor protein p62 markedly increases p62's binding affinity for Keap1, sequestering Keap1 and thereby preventing Keap1-mediated Nrf2 ubiquitination and degradation. This couples selective autophagy to Nrf2 activation. Co-IP, phosphorylation assays, genetic deletion/rescue experiments, cell-based ubiquitination assays Molecular cell High 24011591
2015 Structural studies establish that Keap1 assembles as a homodimer with Cul3 to form a Cullin-RING E3 ligase. Crystal structures define two-site (DLG and ETGE motif) binding of Nrf2 to the Kelch domain of Keap1, providing a rational 3D model for how Nrf2 is presented for ubiquitination and how inducer-mediated cysteine modification disrupts this. X-ray crystallography, structural biology, protein-protein interaction studies Free radical biology & medicine High 26057936
2018 Itaconate, an endogenous macrophage metabolite, directly alkylates multiple cysteine residues on KEAP1 (Cys151, 257, 273, 288, and 297), thereby activating Nrf2 and promoting anti-inflammatory gene expression. This covalent modification was confirmed by mass spectrometry. Mass spectrometry-based covalent modification mapping, cell-based Nrf2 activation assays, genetic knockouts (Irg1/Acod1 KO macrophages) Nature High 29590092
2018 Inhibition of the glycolytic enzyme PGK1 leads to accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink (MICA) between proximal Cys and Arg residues. This post-translational modification induces KEAP1 dimerization and causes NRF2 accumulation and transcriptional activation, directly linking glycolysis to KEAP1-NRF2 signaling. Small-molecule inhibitor studies, mass spectrometry, biochemical crosslinking assays, cell-based NRF2 reporter assays Nature High 30323285
2020 Curcumin binds to Keap1 Cys151 (confirmed by mass spectrometry), and mutation of Cys151 to Ser markedly reduces curcumin-induced Nrf2 transactivation. Curcumin inhibits Keap1-mediated ubiquitination and 26S proteasomal degradation of Nrf2, stabilizing the protein. The electrophilic α,β-unsaturated carbonyl moiety is essential for this modification. Mass spectrometry, site-directed mutagenesis (C151S), ubiquitination assay, reporter gene assay Biochemical pharmacology High 31972171
2014 Real-time FRET-FLIM imaging of Keap1-Nrf2 interactions in single living cells supports a 'cyclic sequential attachment and regeneration' (conformation cycling) model of Keap1-mediated Nrf2 degradation, in which Keap1 continuously targets Nrf2 but loses this ability upon cysteine modification by inducers such as sulforaphane. Förster resonance energy transfer (FRET), multiphoton fluorescence lifetime imaging microscopy (FLIM) in live cells Biotechnology advances Medium 24681086
2020 NBR1, an autophagy receptor structurally similar to p62, promotes p62-liquid droplet formation and accumulation of phosphorylated p62, which is required for non-canonical Keap1-Nrf2 pathway activation. Loss of Nbr1 suppresses both p62-liquid droplet formation and p62-dependent Nrf2 activation during oxidative stress. Genetic knockout (Nbr1-KO cells/mice), overexpression, live-cell imaging of liquid droplets, co-IP, Nrf2 target gene assays EMBO reports Medium 31916398
2022 Chaperone-mediated autophagy (CMA) directly degrades Keap1 via the lysosomal pathway. Activated CMA increases Nrf2 levels by degrading Keap1, promoting Nrf2 nuclear translocation and antioxidant gene expression. Together with Nrf2-dependent LAMP2A transcription, this forms a feed-forward loop between CMA and Nrf2. CMA activation/inhibition experiments, Keap1 degradation assays (lysosomal fractionation), siRNA knockdown, Nrf2 nuclear translocation imaging Aging cell Medium 35535673
2023 PINK1 regulates Keap1 localization and Keap1-dependent ubiquitylation of the ER-phagy receptor Rtnl1 to facilitate selective ER clearance by autophagy (ER-phagy) during development. Keap1 and Cul3 act downstream of PINK1 in ER clearance, while Parkin (downstream of PINK1 in mitophagy) has the opposite function in ER clearance. PINK1 regulates the balance of Keap1- and Parkin-dependent ubiquitylation to determine which organelle is removed. Genetic epistasis in Drosophila, ubiquitylation assays, confocal microscopy for Keap1 localization, genetic rescue experiments Cell High 37633267
2018 AMPK physically associates with a protein complex containing PGAM5 and Keap1, facilitating Keap1-mediated PGAM5 ubiquitination upon necroptosis induction. Activation of AMPK promotes Keap1-mediated PGAM5 degradation to protect against necroptosis. Co-immunoprecipitation, ubiquitination assay, genetic dominant-negative and constitutively active AMPK constructs, shRNA knockdown, Langendorff heart perfusion model International journal of cardiology Medium 29579593
2020 GULP1 is a Keap1-binding protein that maintains actin cytoskeleton architecture and helps Keap1 sequester NRF2 in the cytoplasm of urothelial carcinoma cells. Silencing GULP1 facilitates nuclear accumulation of NRF2, constitutive activation of NRF2 signaling, and cisplatin resistance. Co-IP (GULP1-Keap1 interaction), siRNA knockdown, NRF2 nuclear translocation assay, in vivo xenograft, promoter methylation analysis Science signaling Medium 32817372
2023 Keap1 deficiency induces aberrant activation of TFEB/TFE3-dependent lysosomal biogenesis in a cell-autonomous and evolutionarily conserved manner. This identifies a role for the KEAP1-NRF2 pathway in the regulation of lysosomal biogenesis beyond its canonical antioxidant function. Genetic Keap1 knockout in zebrafish and mammalian cells, lysosome quantification, transcriptomic analysis, NRF2 rescue experiments Proceedings of the National Academy of Sciences of the United States of America Medium 37216554
2015 MicroRNA-7 (miR-7) represses Keap1 expression by targeting the 3'-UTR of Keap1 mRNA, leading to increased Nrf2 activity (elevated HO-1, GCLM expression and enhanced Nrf2 nuclear localization) and protection against oxidative stress in neuroblastoma cells. miRNA target reporter assay (3'-UTR luciferase), qRT-PCR, Nrf2 nuclear localization imaging, siRNA and miRNA mimic transfection Free radical biology & medicine Medium 26453926
2017 CRISPR-Cas9 deletion screens identified that loss of KEAP1 abrogates ROS increases induced by RTK/MAPK pathway inhibitors and alters cell metabolism, allowing proliferation in the absence of MAPK signaling. Loss of KEAP1 modulates response to BRAF, MEK, EGFR, and ALK inhibitors in multiple lung cancer cell contexts. CRISPR-Cas9 gene deletion screens, ROS measurement, metabolic assays, pharmacological inhibitor studies eLife Medium 28145866
2023 PRMT5 methylates KEAP1, which downregulates NRF2 and its downstream targets. PRMT5-mediated KEAP1 methylation modulates iron metabolism and drives resistance to ferroptosis in triple-negative breast cancer. Biochemical methylation assays (PRMT5-KEAP1), co-IP, functional ferroptosis assays, genetic knockdown Journal for immunotherapy of cancer Medium 37380368
2023 DDRGK1 competitively binds to KEAP1 and inhibits KEAP1-mediated NRF2 ubiquitination. DDRGK1 knockout increases Keap1-CUL3-dependent NRF2 ubiquitination and destabilization, leading to ROS accumulation and enhanced chemosensitivity. Co-IP (DDRGK1-KEAP1 interaction), ubiquitination assay, CRISPR-Cas9 knockout, in vivo xenograft Advanced science Medium 36965071
2022 KEAP1 can be exploited as an E3 ligase for targeted protein degradation (PROTAC) technology. KEAP1-recruiting degraders successfully degraded BET family proteins and murine FAK, but KEAP1 had a narrow target scope compared to CRBN. Linking a KEAP1-binding ligand to a CRBN-binding ligand induced KEAP1 self-degradation rather than CRBN degradation. PROTAC/bivalent degrader synthesis, cell-based protein degradation assays, E3 ligase recruitment biochemistry Cell chemical biology Medium 36070758
2023 Hydrogen sulfide (H2S) S-sulfhydrates Keap1 cysteine residues, promoting Nrf2 nuclear translocation and transcription of SLC7A11 and GPX4, thereby activating the SLC7A11/GSH/GPx4 antioxidant pathway and protecting cardiomyocytes from ferroptosis. S-sulfhydration assay (modified biotin-switch), Nrf2 nuclear translocation imaging, cardiac-specific CSE knockout mouse model, functional ferroptosis assays Redox biology Medium 38359744

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annual review of pharmacology and toxicology 2956 16968214
2018 Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 1491 29590092
2004 Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends in molecular medicine 1447 15519281
2009 Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free radical biology & medicine 1319 19666107
2020 The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway. Molecular and cellular biology 1202 32284348
2019 Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nature reviews. Drug discovery 1131 30610225
2013 The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox biology 1063 24024136
2013 The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes & development 1060 24142871
2013 Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Molecular cell 992 24011591
2005 Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxidants & redox signaling 886 15706085
2006 Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug metabolism reviews 883 17145701
2012 The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochemical pharmacology 843 23219527
2011 The cytoprotective role of the Keap1-Nrf2 pathway. Archives of toxicology 824 21365312
2015 Molecular basis of the Keap1-Nrf2 system. Free radical biology & medicine 794 26117331
2009 NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends in biochemical sciences 727 19321346
2013 Toward clinical application of the Keap1-Nrf2 pathway. Trends in pharmacological sciences 582 23664668
2017 Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis 565 28805788
2015 Structural basis of Keap1 interactions with Nrf2. Free radical biology & medicine 479 26057936
2017 The KEAP1-NRF2 System in Cancer. Frontiers in oncology 432 28523248
2021 Nrf2/Keap1/ARE signaling: Towards specific regulation. Life sciences 406 34732330
2021 The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging. Oxidative medicine and cellular longevity 390 34012501
2022 Signal amplification in the KEAP1-NRF2-ARE antioxidant response pathway. Redox biology 348 35792437
2018 A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling. Nature 288 30323285
2016 Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants. Archives of biochemistry and biophysics 265 27497696
2011 Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer. Cancer research 234 21676886
2004 Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers. Mutation research 234 15476857
2023 Molecular Basis of the KEAP1-NRF2 Signaling Pathway. Molecules and cells 223 36994473
2023 The KEAP1-NRF2 pathway: Targets for therapy and role in cancer. Redox biology 222 37146513
2017 KEAP1 and Done? Targeting the NRF2 Pathway with Sulforaphane. Trends in food science & technology 221 29242678
2020 Beyond repression of Nrf2: An update on Keap1. Free radical biology & medicine 218 32234331
2015 Epigenetic regulation of Keap1-Nrf2 signaling. Free radical biology & medicine 212 26117320
2020 Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer. Cell reports 200 33264619
2014 The Keap1-Nrf2 system and diabetes mellitus. Archives of biochemistry and biophysics 186 25528168
2020 Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway. Oxidative medicine and cellular longevity 184 32377290
2024 Hydrogen sulfide protects cardiomyocytes from doxorubicin-induced ferroptosis through the SLC7A11/GSH/GPx4 pathway by Keap1 S-sulfhydration and Nrf2 activation. Redox biology 174 38359744
2015 KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity. The Biochemical journal 162 26205490
2020 The KEAP1-NRF2 System as a Molecular Target of Cancer Treatment. Cancers 155 33375248
2017 Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression. American journal of nephrology 155 28502971
2016 Multiple regulations of Keap1/Nrf2 system by dietary phytochemicals. Molecular nutrition & food research 143 27523917
2017 KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. eLife 141 28145866
2019 Recent Advances of Natural Polyphenols Activators for Keap1-Nrf2 Signaling Pathway. Chemistry & biodiversity 138 31482617
2014 Role of the Keap1-Nrf2 pathway in cancer. Advances in cancer research 136 24974185
2020 Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification. Biochemical pharmacology 135 31972171
2015 The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic. Biochemical Society transactions 134 26551713
2014 Monitoring Keap1-Nrf2 interactions in single live cells. Biotechnology advances 131 24681086
2018 Clinical and Pathological Characteristics of KEAP1- and NFE2L2-Mutated Non-Small Cell Lung Carcinoma (NSCLC). Clinical cancer research : an official journal of the American Association for Cancer Research 129 29615460
2023 KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance. Cell reports 127 37889752
2009 Cysteine-based regulation of the CUL3 adaptor protein Keap1. Toxicology and applied pharmacology 126 19560482
2014 The emerging role of redox-sensitive Nrf2-Keap1 pathway in diabetes. Pharmacological research 116 25447793
2015 Emerging functional cross-talk between the Keap1-Nrf2 system and mitochondria. Journal of clinical biochemistry and nutrition 115 25759513
2023 MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1/NRF2 interaction. Redox biology 114 38100883
2021 The Role of NRF2/KEAP1 Signaling Pathway in Cancer Metabolism. International journal of molecular sciences 114 33922165
2015 MicroRNA-7 activates Nrf2 pathway by targeting Keap1 expression. Free radical biology & medicine 114 26453926
2020 NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system. EMBO reports 110 31916398
2015 Role of the Keap1/Nrf2 pathway in neurodegenerative diseases. Pathology international 107 25707882
2023 Modulation of NRF2/KEAP1 Signaling in Preeclampsia. Cells 103 37296665
2016 Keap1 as the redox sensor of the antioxidant response. Archives of biochemistry and biophysics 93 27769838
2012 Keap1: one stone kills three birds Nrf2, IKKβ and Bcl-2/Bcl-xL. Cancer letters 93 22743616
2020 Keap1-Nrf2 signaling pathway in angiogenesis and vascular diseases. Journal of tissue engineering and regenerative medicine 90 32336035
2018 The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones. Molecules (Basel, Switzerland) 90 30037040
2011 Regulation of the Keap1/Nrf2 system by chemopreventive sulforaphane: implications of posttranslational modifications. Annals of the New York Academy of Sciences 90 21793854
2017 WDR23 regulates NRF2 independently of KEAP1. PLoS genetics 89 28453520
2022 Exploring the target scope of KEAP1 E3 ligase-based PROTACs. Cell chemical biology 82 36070758
2023 The KEAP1-NRF2 System and Neurodegenerative Diseases. Antioxidants & redox signaling 81 36930785
2020 Epigenetic Regulation of NRF2/KEAP1 by Phytochemicals. Antioxidants (Basel, Switzerland) 79 32938017
2021 The KEAP1-NRF2 System in Healthy Aging and Longevity. Antioxidants (Basel, Switzerland) 77 34943032
2022 Chaperone-mediated autophagy degrades Keap1 and promotes Nrf2-mediated antioxidative response. Aging cell 72 35535673
2022 UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis. Journal of experimental & clinical cancer research : CR 72 36419136
2015 Dysregulation of the Keap1-Nrf2 pathway in cancer. Biochemical Society transactions 72 26551706
2020 Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation. Cell communication and signaling : CCS 71 32576270
2023 PRMT5 reduces immunotherapy efficacy in triple-negative breast cancer by methylating KEAP1 and inhibiting ferroptosis. Journal for immunotherapy of cancer 69 37380368
2020 Clinical Implications of KEAP1-NFE2L2 Mutations in NSCLC. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 69 33307193
2002 Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase. Free radical biology & medicine 69 11909699
2023 Targeting the NRF2/KEAP1 pathway in cervical and endometrial cancers. European journal of pharmacology 67 36641100
2020 Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1. Nature cancer 64 34414377
2023 DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 60 36965071
2022 KEAP1-Mutant NSCLC: The Catastrophic Failure of a Cell-Protecting Hub. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 57 35351670
2017 The see-saw of Keap1-Nrf2 pathway in cancer. Critical reviews in oncology/hematology 57 28693803
2023 Mangiferin attenuates osteoporosis by inhibiting osteoblastic ferroptosis through Keap1/Nrf2/SLC7A11/GPX4 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 56 38176266
2024 Modulation of NRF2/KEAP1 Signaling by Phytotherapeutics in Periodontitis. Antioxidants (Basel, Switzerland) 51 39456522
2024 Regulation of Keap1-Nrf2 signaling in health and diseases. Molecular biology reports 48 39001962
2023 PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development. Cell 48 37633267
2020 Functional, proteomic and bioinformatic analyses of Nrf2- and Keap1- null skeletal muscle. The Journal of physiology 47 32893883
2021 Keap1/Nrf2 Signaling Pathway. Antioxidants (Basel, Switzerland) 45 34067331
2015 Keap1-Nrf2 signalling in pancreatic cancer. The international journal of biochemistry & cell biology 45 26117456
2018 "Keaping" a lid on lung cancer: the Keap1-Nrf2 pathway. Cell cycle (Georgetown, Tex.) 44 30009666
2015 Applications of the Keap1-Nrf2 system for gene and cell therapy. Free radical biology & medicine 44 26164630
2014 Baicalein modulates Nrf2/Keap1 system in both Keap1-dependent and Keap1-independent mechanisms. Archives of biochemistry and biophysics 43 24704364
2019 Keap1/Nrf2 Signaling: A New Player in Thyroid Pathophysiology and Thyroid Cancer. Frontiers in endocrinology 42 31428048
2018 AMP-activated protein kinase protects against necroptosis via regulation of Keap1-PGAM5 complex. International journal of cardiology 41 29579593
2022 The Role of KEAP1-NRF2 System in Atopic Dermatitis and Psoriasis. Antioxidants (Basel, Switzerland) 39 35883888
2022 The KEAP1-NRF2 System and Esophageal Cancer. Cancers 37 36230622
2021 KEAP1/NRF2 (NFE2L2) mutations in NSCLC - Fuel for a superresistant phenotype? Lung cancer (Amsterdam, Netherlands) 36 34303275
2014 Keap1 inhibition attenuates glomerulosclerosis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 36 24523358
2024 Post-translational modifications of Keap1: the state of the art. Frontiers in cell and developmental biology 35 38259518
2020 GULP1 regulates the NRF2-KEAP1 signaling axis in urothelial carcinoma. Science signaling 35 32817372
2018 Importance of the Keap1-Nrf2 pathway in NSCLC: Is it a possible biomarker? Biomedical reports 35 30345037
2023 The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis. Proceedings of the National Academy of Sciences of the United States of America 32 37216554
2018 Cloning and Functional Analysis of CncC and Keap1 Genes in Silkworm. Journal of agricultural and food chemistry 31 29482325
2015 Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway. Biochemical Society transactions 30 26551704

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