{"gene":"KEAP1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2002,"finding":"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.","method":"Immunoprecipitation (co-IP), indirect immunofluorescence, reporter gene assay, overexpression/dominant-negative experiments","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, reporter assay, and subcellular localization in one study; multiple orthogonal methods in single lab","pmids":["11909699"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Biochemical assays for ubiquitination, proteasome inhibition experiments, genetic studies in keap1-knockout mice","journal":"Antioxidants & redox signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across multiple labs, genetic and biochemical evidence including knockout mice and ubiquitination assays","pmids":["15706085","15519281","17145701"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Site-directed mutagenesis, proteomic analysis, biochemical functional assays","journal":"Toxicology and applied pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis with functional readout, supported by proteomic analysis, single lab with multiple orthogonal methods","pmids":["19560482"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Kinase phosphorylation assays, mutagenesis, nuclear fractionation, co-IP","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple biochemical assays described in single review/study context; signaling cascade well-supported but some steps inferred from indirect evidence","pmids":["19666107"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-IP, phosphorylation assays, genetic deletion/rescue experiments, cell-based ubiquitination assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, phosphorylation mapping, mTORC1-dependent assays, multiple genetic models in a single rigorous study","pmids":["24011591"],"is_preprint":false},{"year":2015,"finding":"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.","method":"X-ray crystallography, structural biology, protein-protein interaction studies","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional validation; replicated across multiple structural studies","pmids":["26057936"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Mass spectrometry-based covalent modification mapping, cell-based Nrf2 activation assays, genetic knockouts (Irg1/Acod1 KO macrophages)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct chemical modification mapped by MS, functional validation with genetic KO and rescue, multiple orthogonal methods","pmids":["29590092"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Small-molecule inhibitor studies, mass spectrometry, biochemical crosslinking assays, cell-based NRF2 reporter assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — chemical mechanism identified by MS, functional validation with multiple orthogonal methods in single rigorous study","pmids":["30323285"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Mass spectrometry, site-directed mutagenesis (C151S), ubiquitination assay, reporter gene assay","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS-confirmed site-specific covalent modification plus mutagenesis with functional readout in a single focused study","pmids":["31972171"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Förster resonance energy transfer (FRET), multiphoton fluorescence lifetime imaging microscopy (FLIM) in live cells","journal":"Biotechnology advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell protein-protein interaction dynamics measured by FRET-FLIM, single lab with advanced imaging approach","pmids":["24681086"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Genetic knockout (Nbr1-KO cells/mice), overexpression, live-cell imaging of liquid droplets, co-IP, Nrf2 target gene assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype, multiple methods in single lab study","pmids":["31916398"],"is_preprint":false},{"year":2022,"finding":"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.","method":"CMA activation/inhibition experiments, Keap1 degradation assays (lysosomal fractionation), siRNA knockdown, Nrf2 nuclear translocation imaging","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lysosomal fractionation and functional rescue experiments in single lab, multiple orthogonal methods","pmids":["35535673"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Genetic epistasis in Drosophila, ubiquitylation assays, confocal microscopy for Keap1 localization, genetic rescue experiments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous genetic epistasis in Drosophila model with functional ubiquitylation assays and localization imaging; multiple orthogonal methods","pmids":["37633267"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, genetic dominant-negative and constitutively active AMPK constructs, shRNA knockdown, Langendorff heart perfusion model","journal":"International journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating ternary complex, ubiquitination assay, multiple functional genetic tools in single lab","pmids":["29579593"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-IP (GULP1-Keap1 interaction), siRNA knockdown, NRF2 nuclear translocation assay, in vivo xenograft, promoter methylation analysis","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for interaction, KD with functional cellular phenotype, in vivo validation; single lab study","pmids":["32817372"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Genetic Keap1 knockout in zebrafish and mammalian cells, lysosome quantification, transcriptomic analysis, NRF2 rescue experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined cellular/organismal phenotype, evolutionary conservation across models","pmids":["37216554"],"is_preprint":false},{"year":2015,"finding":"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.","method":"miRNA target reporter assay (3'-UTR luciferase), qRT-PCR, Nrf2 nuclear localization imaging, siRNA and miRNA mimic transfection","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR targeting confirmed, multiple functional readouts; single lab study","pmids":["26453926"],"is_preprint":false},{"year":2017,"finding":"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.","method":"CRISPR-Cas9 gene deletion screens, ROS measurement, metabolic assays, pharmacological inhibitor studies","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-scale CRISPR screen with mechanistic follow-up (ROS assay, metabolic analysis); single study","pmids":["28145866"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Biochemical methylation assays (PRMT5-KEAP1), co-IP, functional ferroptosis assays, genetic knockdown","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical methylation shown with functional consequences; single lab study","pmids":["37380368"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP (DDRGK1-KEAP1 interaction), ubiquitination assay, CRISPR-Cas9 knockout, in vivo xenograft","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with genetic KO validation in vivo; single lab study","pmids":["36965071"],"is_preprint":false},{"year":2022,"finding":"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.","method":"PROTAC/bivalent degrader synthesis, cell-based protein degradation assays, E3 ligase recruitment biochemistry","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based degradation assays with multiple targets; single focused mechanistic study","pmids":["36070758"],"is_preprint":false},{"year":2023,"finding":"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.","method":"S-sulfhydration assay (modified biotin-switch), Nrf2 nuclear translocation imaging, cardiac-specific CSE knockout mouse model, functional ferroptosis assays","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM (S-sulfhydration) biochemically detected, genetic KO/rescue model, multiple functional readouts; single lab","pmids":["38359744"],"is_preprint":false}],"current_model":"KEAP1 is a homodimeric, cysteine-rich substrate adaptor for a CUL3-RBX1 E3 ubiquitin ligase that constitutively ubiquitinates and targets NRF2 for proteasomal degradation under basal conditions; oxidative, electrophilic, or metabolic stress covalently modifies critical sensor cysteines (principally Cys151, Cys273, Cys288) on KEAP1—via alkylation, S-sulfhydration, methylglyoxal-derived crosslinking, or other modifications—causing conformational changes that impair Nrf2 ubiquitination, allowing newly synthesized NRF2 to accumulate, translocate to the nucleus, and activate cytoprotective gene transcription; KEAP1 also targets additional substrates including PGAM5 and regulates ER-phagy via PINK1-directed ubiquitylation of Rtnl1, while its activity is further modulated by competitive binding of proteins such as phospho-p62, GULP1, and DDRGK1, by CMA-mediated lysosomal degradation of KEAP1 itself, and by post-translational modifications including PRMT5-mediated methylation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2002,"claim":"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","pmids":["11909699"],"confidence":"High","gaps":["Did not define the enzymatic mechanism by which KEAP1 controls NRF2 levels","No molecular identification of the redox-sensing residues"]},{"year":2005,"claim":"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","pmids":["15706085","15519281","17145701"],"confidence":"High","gaps":["Did not pinpoint which cysteines act as the stress sensor","Structural basis of NRF2 presentation unresolved"]},{"year":2009,"claim":"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","pmids":["19560482"],"confidence":"High","gaps":["Did not establish whether different inducers preferentially target different cysteines","Conformational changes not directly visualized"]},{"year":2009,"claim":"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","pmids":["19666107"],"confidence":"Medium","gaps":["Some cascade steps inferred from indirect evidence","Relative contribution of cysteine versus phosphorylation arms not quantified"]},{"year":2014,"claim":"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","pmids":["24681086"],"confidence":"Medium","gaps":["Single advanced-imaging approach from one lab","Does not directly link dynamics to ubiquitin transfer kinetics"]},{"year":2015,"claim":"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","pmids":["26057936"],"confidence":"High","gaps":["Static structures do not capture the inducer-triggered conformational transition directly","Structures of modified-cysteine states not defined"]},{"year":2013,"claim":"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","pmids":["24011591"],"confidence":"High","gaps":["Did not establish in vivo physiological triggers of this branch","Stoichiometry of competition with NRF2 unresolved"]},{"year":2018,"claim":"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","pmids":["29590092","30323285"],"confidence":"High","gaps":["Did not resolve which physiological conditions dominate in vivo","Quantitative thresholds for activation per modification unclear"]},{"year":2018,"claim":"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","pmids":["29579593"],"confidence":"Medium","gaps":["Direct versus complex-mediated ubiquitin transfer to PGAM5 not fully separated","Single lab study"]},{"year":2020,"claim":"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","pmids":["32817372","31916398"],"confidence":"Medium","gaps":["Reciprocal validation of some interactions limited","Generality across cell types untested"]},{"year":2020,"claim":"Confirmed curcumin as a Cys151-directed electrophilic modifier that stabilizes NRF2 by inhibiting KEAP1-mediated ubiquitination.","evidence":"MS, C151S mutagenesis, ubiquitination and reporter assays","pmids":["31972171"],"confidence":"High","gaps":["Selectivity for Cys151 over other cysteines not exhaustively mapped"]},{"year":2022,"claim":"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","pmids":["35535673"],"confidence":"Medium","gaps":["Recognition motif on KEAP1 for CMA not defined","Physiological triggers of CMA-mediated KEAP1 turnover unclear"]},{"year":2022,"claim":"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","pmids":["36070758"],"confidence":"Medium","gaps":["Structural basis of narrow target scope unresolved","Determinants of KEAP1 self-degradation undefined"]},{"year":2023,"claim":"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","pmids":["37633267"],"confidence":"High","gaps":["Mechanism of PINK1 control over KEAP1 localization not fully defined","Conservation of Rtnl1 substrate role in mammals untested here"]},{"year":2023,"claim":"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","pmids":["36965071","37380368"],"confidence":"Medium","gaps":["Methylation site(s) on KEAP1 not pinpointed","Interplay with cysteine sensing not addressed"]},{"year":2023,"claim":"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","pmids":["37216554"],"confidence":"Medium","gaps":["Direct molecular link between NRF2 and TFEB/TFE3 not defined","Whether KEAP1 acts on lysosomal regulators directly unresolved"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model integrating the diverse KEAP1 modifications","Determinants of substrate choice between NRF2, PGAM5, and Rtnl1 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,13,12]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2,6,7,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,14]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,2,6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,5,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,11,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13,18,21]}],"complexes":["KEAP1-CUL3-RBX1 E3 ubiquitin ligase","KEAP1-PGAM5-AMPK complex"],"partners":["NFE2L2","CUL3","SQSTM1","PGAM5","GULP1","DDRGK1","NBR1","PRMT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14145","full_name":"Kelch-like ECH-associated protein 1","aliases":["Cytosolic inhibitor of Nrf2","INrf2","Kelch-like protein 19"],"length_aa":624,"mass_kda":69.7,"function":"Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination (PubMed:14585973, PubMed:15379550, PubMed:15572695, PubMed:15601839, PubMed:15983046, PubMed:37339955). KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes (PubMed:15601839, PubMed:16006525). In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (PubMed:16006525, PubMed:17127771, PubMed:18251510, PubMed:19489739, PubMed:29590092). In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2 (PubMed:20452972). The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation (PubMed:28380357). The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome (PubMed:15379550, PubMed:17046835)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q14145/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KEAP1","classification":"Not Classified","n_dependent_lines":257,"n_total_lines":1208,"dependency_fraction":0.21274834437086093},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000079999","cell_line_id":"CID001849","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"GSPT1","stoichiometry":0.2},{"gene":"PTMA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001849","total_profiled":1310},"omim":[{"mim_id":"621451","title":"SMALL NUCLEOLAR RNA HOST GENE 12; SNHG12","url":"https://www.omim.org/entry/621451"},{"mim_id":"619926","title":"KELCH-LIKE FAMILY, MEMBER 18; KLHL18","url":"https://www.omim.org/entry/619926"},{"mim_id":"617744","title":"IMMUNODEFICIENCY, DEVELOPMENTAL DELAY, AND HYPOHOMOCYSTEINEMIA; IMDDHH","url":"https://www.omim.org/entry/617744"},{"mim_id":"614939","title":"PHOSPHOGLYCERATE MUTASE FAMILY, MEMBER 5; PGAM5","url":"https://www.omim.org/entry/614939"},{"mim_id":"614522","title":"KELCH-LIKE 12; KLHL12","url":"https://www.omim.org/entry/614522"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Centriolar satellite","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":170.8}],"url":"https://www.proteinatlas.org/search/KEAP1"},"hgnc":{"alias_symbol":["KIAA0132","MGC10630","MGC1114","MGC20887","MGC4407","MGC9454","INrf2","KLHL19"],"prev_symbol":[]},"alphafold":{"accession":"Q14145","domains":[{"cath_id":"3.30.710.10","chopping":"59-178","consensus_level":"high","plddt":93.5329,"start":59,"end":178},{"cath_id":"1.25.40.420","chopping":"229-309","consensus_level":"high","plddt":92.9588,"start":229,"end":309},{"cath_id":"2.120.10.80","chopping":"325-620","consensus_level":"medium","plddt":96.3417,"start":325,"end":620}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14145","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14145-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14145-F1-predicted_aligned_error_v6.png","plddt_mean":90.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KEAP1","jax_strain_url":"https://www.jax.org/strain/search?query=KEAP1"},"sequence":{"accession":"Q14145","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14145.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14145/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14145"}},"corpus_meta":[{"pmid":"16968214","id":"PMC_16968214","title":"Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway.","date":"2007","source":"Annual review of pharmacology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/16968214","citation_count":2956,"is_preprint":false},{"pmid":"29590092","id":"PMC_29590092","title":"Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/29590092","citation_count":1491,"is_preprint":false},{"pmid":"15519281","id":"PMC_15519281","title":"Nrf2-Keap1 defines a physiologically important stress response mechanism.","date":"2004","source":"Trends in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15519281","citation_count":1447,"is_preprint":false},{"pmid":"19666107","id":"PMC_19666107","title":"Nrf2:INrf2 (Keap1) signaling in oxidative stress.","date":"2009","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19666107","citation_count":1319,"is_preprint":false},{"pmid":"32284348","id":"PMC_32284348","title":"The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway.","date":"2020","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32284348","citation_count":1202,"is_preprint":false},{"pmid":"30610225","id":"PMC_30610225","title":"Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases.","date":"2019","source":"Nature reviews. Drug discovery","url":"https://pubmed.ncbi.nlm.nih.gov/30610225","citation_count":1131,"is_preprint":false},{"pmid":"24024136","id":"PMC_24024136","title":"The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer.","date":"2013","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/24024136","citation_count":1063,"is_preprint":false},{"pmid":"24142871","id":"PMC_24142871","title":"The emerging role of the Nrf2-Keap1 signaling pathway in cancer.","date":"2013","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/24142871","citation_count":1060,"is_preprint":false},{"pmid":"24011591","id":"PMC_24011591","title":"Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24011591","citation_count":992,"is_preprint":false},{"pmid":"15706085","id":"PMC_15706085","title":"Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation.","date":"2005","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/15706085","citation_count":886,"is_preprint":false},{"pmid":"17145701","id":"PMC_17145701","title":"Mechanistic studies of the Nrf2-Keap1 signaling pathway.","date":"2006","source":"Drug metabolism reviews","url":"https://pubmed.ncbi.nlm.nih.gov/17145701","citation_count":883,"is_preprint":false},{"pmid":"23219527","id":"PMC_23219527","title":"The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation.","date":"2012","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23219527","citation_count":843,"is_preprint":false},{"pmid":"21365312","id":"PMC_21365312","title":"The cytoprotective role of the Keap1-Nrf2 pathway.","date":"2011","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/21365312","citation_count":824,"is_preprint":false},{"pmid":"26117331","id":"PMC_26117331","title":"Molecular basis of the Keap1-Nrf2 system.","date":"2015","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26117331","citation_count":794,"is_preprint":false},{"pmid":"19321346","id":"PMC_19321346","title":"NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer.","date":"2009","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19321346","citation_count":727,"is_preprint":false},{"pmid":"23664668","id":"PMC_23664668","title":"Toward clinical application of the Keap1-Nrf2 pathway.","date":"2013","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23664668","citation_count":582,"is_preprint":false},{"pmid":"28805788","id":"PMC_28805788","title":"Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis.","date":"2017","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28805788","citation_count":565,"is_preprint":false},{"pmid":"26057936","id":"PMC_26057936","title":"Structural basis of Keap1 interactions with Nrf2.","date":"2015","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26057936","citation_count":479,"is_preprint":false},{"pmid":"28523248","id":"PMC_28523248","title":"The KEAP1-NRF2 System in Cancer.","date":"2017","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28523248","citation_count":432,"is_preprint":false},{"pmid":"34732330","id":"PMC_34732330","title":"Nrf2/Keap1/ARE signaling: Towards specific regulation.","date":"2021","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34732330","citation_count":406,"is_preprint":false},{"pmid":"34012501","id":"PMC_34012501","title":"The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34012501","citation_count":390,"is_preprint":false},{"pmid":"35792437","id":"PMC_35792437","title":"Signal amplification in the KEAP1-NRF2-ARE antioxidant response pathway.","date":"2022","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/35792437","citation_count":348,"is_preprint":false},{"pmid":"30323285","id":"PMC_30323285","title":"A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/30323285","citation_count":288,"is_preprint":false},{"pmid":"27497696","id":"PMC_27497696","title":"Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants.","date":"2016","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/27497696","citation_count":265,"is_preprint":false},{"pmid":"15476857","id":"PMC_15476857","title":"Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers.","date":"2004","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/15476857","citation_count":234,"is_preprint":false},{"pmid":"21676886","id":"PMC_21676886","title":"Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21676886","citation_count":234,"is_preprint":false},{"pmid":"36994473","id":"PMC_36994473","title":"Molecular Basis of the KEAP1-NRF2 Signaling Pathway.","date":"2023","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/36994473","citation_count":223,"is_preprint":false},{"pmid":"37146513","id":"PMC_37146513","title":"The KEAP1-NRF2 pathway: Targets for therapy and role in cancer.","date":"2023","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/37146513","citation_count":222,"is_preprint":false},{"pmid":"29242678","id":"PMC_29242678","title":"KEAP1 and Done? Targeting the NRF2 Pathway with Sulforaphane.","date":"2017","source":"Trends in food science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/29242678","citation_count":221,"is_preprint":false},{"pmid":"32234331","id":"PMC_32234331","title":"Beyond repression of Nrf2: An update on Keap1.","date":"2020","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32234331","citation_count":218,"is_preprint":false},{"pmid":"26117320","id":"PMC_26117320","title":"Epigenetic regulation of Keap1-Nrf2 signaling.","date":"2015","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26117320","citation_count":212,"is_preprint":false},{"pmid":"33264619","id":"PMC_33264619","title":"Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33264619","citation_count":200,"is_preprint":false},{"pmid":"25528168","id":"PMC_25528168","title":"The Keap1-Nrf2 system and diabetes mellitus.","date":"2014","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/25528168","citation_count":186,"is_preprint":false},{"pmid":"32377290","id":"PMC_32377290","title":"Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway.","date":"2020","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/32377290","citation_count":184,"is_preprint":false},{"pmid":"38359744","id":"PMC_38359744","title":"Hydrogen sulfide protects cardiomyocytes from doxorubicin-induced ferroptosis through the SLC7A11/GSH/GPx4 pathway by Keap1 S-sulfhydration and Nrf2 activation.","date":"2024","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/38359744","citation_count":174,"is_preprint":false},{"pmid":"26205490","id":"PMC_26205490","title":"KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity.","date":"2015","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/26205490","citation_count":162,"is_preprint":false},{"pmid":"28502971","id":"PMC_28502971","title":"Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression.","date":"2017","source":"American journal of nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/28502971","citation_count":155,"is_preprint":false},{"pmid":"33375248","id":"PMC_33375248","title":"The KEAP1-NRF2 System as a Molecular Target of Cancer Treatment.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33375248","citation_count":155,"is_preprint":false},{"pmid":"27523917","id":"PMC_27523917","title":"Multiple regulations of Keap1/Nrf2 system by dietary phytochemicals.","date":"2016","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/27523917","citation_count":143,"is_preprint":false},{"pmid":"28145866","id":"PMC_28145866","title":"KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28145866","citation_count":141,"is_preprint":false},{"pmid":"31482617","id":"PMC_31482617","title":"Recent Advances of Natural Polyphenols Activators for Keap1-Nrf2 Signaling Pathway.","date":"2019","source":"Chemistry & biodiversity","url":"https://pubmed.ncbi.nlm.nih.gov/31482617","citation_count":138,"is_preprint":false},{"pmid":"24974185","id":"PMC_24974185","title":"Role of the Keap1-Nrf2 pathway in cancer.","date":"2014","source":"Advances in cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24974185","citation_count":136,"is_preprint":false},{"pmid":"31972171","id":"PMC_31972171","title":"Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification.","date":"2020","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31972171","citation_count":135,"is_preprint":false},{"pmid":"26551713","id":"PMC_26551713","title":"The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic.","date":"2015","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/26551713","citation_count":134,"is_preprint":false},{"pmid":"24681086","id":"PMC_24681086","title":"Monitoring Keap1-Nrf2 interactions in single live cells.","date":"2014","source":"Biotechnology advances","url":"https://pubmed.ncbi.nlm.nih.gov/24681086","citation_count":131,"is_preprint":false},{"pmid":"29615460","id":"PMC_29615460","title":"Clinical and Pathological Characteristics of KEAP1- and NFE2L2-Mutated Non-Small Cell Lung Carcinoma (NSCLC).","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/29615460","citation_count":129,"is_preprint":false},{"pmid":"37889752","id":"PMC_37889752","title":"KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37889752","citation_count":127,"is_preprint":false},{"pmid":"19560482","id":"PMC_19560482","title":"Cysteine-based regulation of the CUL3 adaptor protein Keap1.","date":"2009","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19560482","citation_count":126,"is_preprint":false},{"pmid":"25447793","id":"PMC_25447793","title":"The emerging role of redox-sensitive Nrf2-Keap1 pathway in diabetes.","date":"2014","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/25447793","citation_count":116,"is_preprint":false},{"pmid":"25759513","id":"PMC_25759513","title":"Emerging functional cross-talk between the Keap1-Nrf2 system and mitochondria.","date":"2015","source":"Journal of clinical biochemistry and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/25759513","citation_count":115,"is_preprint":false},{"pmid":"38100883","id":"PMC_38100883","title":"MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1/NRF2 interaction.","date":"2023","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/38100883","citation_count":114,"is_preprint":false},{"pmid":"33922165","id":"PMC_33922165","title":"The Role of NRF2/KEAP1 Signaling Pathway in Cancer Metabolism.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33922165","citation_count":114,"is_preprint":false},{"pmid":"26453926","id":"PMC_26453926","title":"MicroRNA-7 activates Nrf2 pathway by targeting Keap1 expression.","date":"2015","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26453926","citation_count":114,"is_preprint":false},{"pmid":"31916398","id":"PMC_31916398","title":"NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system.","date":"2020","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/31916398","citation_count":110,"is_preprint":false},{"pmid":"25707882","id":"PMC_25707882","title":"Role of the Keap1/Nrf2 pathway in neurodegenerative diseases.","date":"2015","source":"Pathology international","url":"https://pubmed.ncbi.nlm.nih.gov/25707882","citation_count":107,"is_preprint":false},{"pmid":"37296665","id":"PMC_37296665","title":"Modulation of NRF2/KEAP1 Signaling in Preeclampsia.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/37296665","citation_count":103,"is_preprint":false},{"pmid":"22743616","id":"PMC_22743616","title":"Keap1: one stone kills three birds Nrf2, IKKβ and Bcl-2/Bcl-xL.","date":"2012","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/22743616","citation_count":93,"is_preprint":false},{"pmid":"27769838","id":"PMC_27769838","title":"Keap1 as the redox sensor of the antioxidant response.","date":"2016","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/27769838","citation_count":93,"is_preprint":false},{"pmid":"32336035","id":"PMC_32336035","title":"Keap1-Nrf2 signaling pathway in angiogenesis and vascular diseases.","date":"2020","source":"Journal of tissue engineering and regenerative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32336035","citation_count":90,"is_preprint":false},{"pmid":"30037040","id":"PMC_30037040","title":"The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones.","date":"2018","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/30037040","citation_count":90,"is_preprint":false},{"pmid":"21793854","id":"PMC_21793854","title":"Regulation of the Keap1/Nrf2 system by chemopreventive sulforaphane: implications of posttranslational modifications.","date":"2011","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/21793854","citation_count":90,"is_preprint":false},{"pmid":"28453520","id":"PMC_28453520","title":"WDR23 regulates NRF2 independently of KEAP1.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28453520","citation_count":89,"is_preprint":false},{"pmid":"36070758","id":"PMC_36070758","title":"Exploring the target scope of KEAP1 E3 ligase-based PROTACs.","date":"2022","source":"Cell chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/36070758","citation_count":82,"is_preprint":false},{"pmid":"36930785","id":"PMC_36930785","title":"The KEAP1-NRF2 System and Neurodegenerative Diseases.","date":"2023","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/36930785","citation_count":81,"is_preprint":false},{"pmid":"32938017","id":"PMC_32938017","title":"Epigenetic Regulation of NRF2/KEAP1 by Phytochemicals.","date":"2020","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32938017","citation_count":79,"is_preprint":false},{"pmid":"34943032","id":"PMC_34943032","title":"The KEAP1-NRF2 System in Healthy Aging and Longevity.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34943032","citation_count":77,"is_preprint":false},{"pmid":"36419136","id":"PMC_36419136","title":"UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/36419136","citation_count":72,"is_preprint":false},{"pmid":"26551706","id":"PMC_26551706","title":"Dysregulation of the Keap1-Nrf2 pathway in cancer.","date":"2015","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/26551706","citation_count":72,"is_preprint":false},{"pmid":"35535673","id":"PMC_35535673","title":"Chaperone-mediated autophagy degrades Keap1 and promotes Nrf2-mediated antioxidative response.","date":"2022","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/35535673","citation_count":72,"is_preprint":false},{"pmid":"32576270","id":"PMC_32576270","title":"Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation.","date":"2020","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/32576270","citation_count":71,"is_preprint":false},{"pmid":"37380368","id":"PMC_37380368","title":"PRMT5 reduces immunotherapy efficacy in triple-negative breast cancer by methylating KEAP1 and inhibiting ferroptosis.","date":"2023","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37380368","citation_count":69,"is_preprint":false},{"pmid":"11909699","id":"PMC_11909699","title":"Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase.","date":"2002","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11909699","citation_count":69,"is_preprint":false},{"pmid":"33307193","id":"PMC_33307193","title":"Clinical Implications of KEAP1-NFE2L2 Mutations in NSCLC.","date":"2020","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33307193","citation_count":69,"is_preprint":false},{"pmid":"36641100","id":"PMC_36641100","title":"Targeting the NRF2/KEAP1 pathway in cervical and endometrial cancers.","date":"2023","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36641100","citation_count":67,"is_preprint":false},{"pmid":"34414377","id":"PMC_34414377","title":"Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1.","date":"2020","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34414377","citation_count":64,"is_preprint":false},{"pmid":"36965071","id":"PMC_36965071","title":"DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36965071","citation_count":60,"is_preprint":false},{"pmid":"35351670","id":"PMC_35351670","title":"KEAP1-Mutant NSCLC: The Catastrophic Failure of a Cell-Protecting Hub.","date":"2022","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35351670","citation_count":57,"is_preprint":false},{"pmid":"28693803","id":"PMC_28693803","title":"The see-saw of Keap1-Nrf2 pathway in cancer.","date":"2017","source":"Critical reviews in oncology/hematology","url":"https://pubmed.ncbi.nlm.nih.gov/28693803","citation_count":57,"is_preprint":false},{"pmid":"38176266","id":"PMC_38176266","title":"Mangiferin attenuates osteoporosis by inhibiting osteoblastic ferroptosis through Keap1/Nrf2/SLC7A11/GPX4 pathway.","date":"2023","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38176266","citation_count":56,"is_preprint":false},{"pmid":"39456522","id":"PMC_39456522","title":"Modulation of NRF2/KEAP1 Signaling by Phytotherapeutics in Periodontitis.","date":"2024","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39456522","citation_count":51,"is_preprint":false},{"pmid":"37633267","id":"PMC_37633267","title":"PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.","date":"2023","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/37633267","citation_count":48,"is_preprint":false},{"pmid":"39001962","id":"PMC_39001962","title":"Regulation of Keap1-Nrf2 signaling in health and diseases.","date":"2024","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/39001962","citation_count":48,"is_preprint":false},{"pmid":"32893883","id":"PMC_32893883","title":"Functional, proteomic and bioinformatic analyses of Nrf2- and Keap1- null skeletal muscle.","date":"2020","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32893883","citation_count":47,"is_preprint":false},{"pmid":"34067331","id":"PMC_34067331","title":"Keap1/Nrf2 Signaling Pathway.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34067331","citation_count":45,"is_preprint":false},{"pmid":"26117456","id":"PMC_26117456","title":"Keap1-Nrf2 signalling in pancreatic cancer.","date":"2015","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26117456","citation_count":45,"is_preprint":false},{"pmid":"26164630","id":"PMC_26164630","title":"Applications of the Keap1-Nrf2 system for gene and cell therapy.","date":"2015","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26164630","citation_count":44,"is_preprint":false},{"pmid":"30009666","id":"PMC_30009666","title":"\"Keaping\" a lid on lung cancer: the Keap1-Nrf2 pathway.","date":"2018","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/30009666","citation_count":44,"is_preprint":false},{"pmid":"24704364","id":"PMC_24704364","title":"Baicalein modulates Nrf2/Keap1 system in both Keap1-dependent and Keap1-independent mechanisms.","date":"2014","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/24704364","citation_count":43,"is_preprint":false},{"pmid":"31428048","id":"PMC_31428048","title":"Keap1/Nrf2 Signaling: A New Player in Thyroid Pathophysiology and Thyroid Cancer.","date":"2019","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31428048","citation_count":42,"is_preprint":false},{"pmid":"29579593","id":"PMC_29579593","title":"AMP-activated protein kinase protects against necroptosis via regulation of Keap1-PGAM5 complex.","date":"2018","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/29579593","citation_count":41,"is_preprint":false},{"pmid":"35883888","id":"PMC_35883888","title":"The Role of KEAP1-NRF2 System in Atopic Dermatitis and Psoriasis.","date":"2022","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35883888","citation_count":39,"is_preprint":false},{"pmid":"36230622","id":"PMC_36230622","title":"The KEAP1-NRF2 System and Esophageal Cancer.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36230622","citation_count":37,"is_preprint":false},{"pmid":"24523358","id":"PMC_24523358","title":"Keap1 inhibition attenuates glomerulosclerosis.","date":"2014","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/24523358","citation_count":36,"is_preprint":false},{"pmid":"34303275","id":"PMC_34303275","title":"KEAP1/NRF2 (NFE2L2) mutations in NSCLC - Fuel for a superresistant phenotype?","date":"2021","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/34303275","citation_count":36,"is_preprint":false},{"pmid":"38259518","id":"PMC_38259518","title":"Post-translational modifications of Keap1: the state of the art.","date":"2024","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/38259518","citation_count":35,"is_preprint":false},{"pmid":"30345037","id":"PMC_30345037","title":"Importance of the Keap1-Nrf2 pathway in NSCLC: Is it a possible biomarker?","date":"2018","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/30345037","citation_count":35,"is_preprint":false},{"pmid":"32817372","id":"PMC_32817372","title":"GULP1 regulates the NRF2-KEAP1 signaling axis in urothelial carcinoma.","date":"2020","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/32817372","citation_count":35,"is_preprint":false},{"pmid":"37216554","id":"PMC_37216554","title":"The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37216554","citation_count":32,"is_preprint":false},{"pmid":"29482325","id":"PMC_29482325","title":"Cloning and Functional Analysis of CncC and Keap1 Genes in Silkworm.","date":"2018","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29482325","citation_count":31,"is_preprint":false},{"pmid":"26551704","id":"PMC_26551704","title":"Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway.","date":"2015","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/26551704","citation_count":30,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46315,"output_tokens":5585,"usd":0.11136,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14045,"output_tokens":5122,"usd":0.099138,"stage2_stop_reason":"end_turn"},"total_usd":0.210498,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation (co-IP), indirect immunofluorescence, reporter gene assay, overexpression/dominant-negative experiments\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, reporter assay, and subcellular localization in one study; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"11909699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical assays for ubiquitination, proteasome inhibition experiments, genetic studies in keap1-knockout mice\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across multiple labs, genetic and biochemical evidence including knockout mice and ubiquitination assays\",\n      \"pmids\": [\"15706085\", \"15519281\", \"17145701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis, proteomic analysis, biochemical functional assays\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis with functional readout, supported by proteomic analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19560482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Kinase phosphorylation assays, mutagenesis, nuclear fractionation, co-IP\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple biochemical assays described in single review/study context; signaling cascade well-supported but some steps inferred from indirect evidence\",\n      \"pmids\": [\"19666107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, phosphorylation assays, genetic deletion/rescue experiments, cell-based ubiquitination assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, phosphorylation mapping, mTORC1-dependent assays, multiple genetic models in a single rigorous study\",\n      \"pmids\": [\"24011591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, structural biology, protein-protein interaction studies\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional validation; replicated across multiple structural studies\",\n      \"pmids\": [\"26057936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry-based covalent modification mapping, cell-based Nrf2 activation assays, genetic knockouts (Irg1/Acod1 KO macrophages)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct chemical modification mapped by MS, functional validation with genetic KO and rescue, multiple orthogonal methods\",\n      \"pmids\": [\"29590092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Small-molecule inhibitor studies, mass spectrometry, biochemical crosslinking assays, cell-based NRF2 reporter assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — chemical mechanism identified by MS, functional validation with multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"30323285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry, site-directed mutagenesis (C151S), ubiquitination assay, reporter gene assay\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS-confirmed site-specific covalent modification plus mutagenesis with functional readout in a single focused study\",\n      \"pmids\": [\"31972171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Förster resonance energy transfer (FRET), multiphoton fluorescence lifetime imaging microscopy (FLIM) in live cells\",\n      \"journal\": \"Biotechnology advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell protein-protein interaction dynamics measured by FRET-FLIM, single lab with advanced imaging approach\",\n      \"pmids\": [\"24681086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic knockout (Nbr1-KO cells/mice), overexpression, live-cell imaging of liquid droplets, co-IP, Nrf2 target gene assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype, multiple methods in single lab study\",\n      \"pmids\": [\"31916398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"CMA activation/inhibition experiments, Keap1 degradation assays (lysosomal fractionation), siRNA knockdown, Nrf2 nuclear translocation imaging\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lysosomal fractionation and functional rescue experiments in single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35535673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic epistasis in Drosophila, ubiquitylation assays, confocal microscopy for Keap1 localization, genetic rescue experiments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous genetic epistasis in Drosophila model with functional ubiquitylation assays and localization imaging; multiple orthogonal methods\",\n      \"pmids\": [\"37633267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, genetic dominant-negative and constitutively active AMPK constructs, shRNA knockdown, Langendorff heart perfusion model\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating ternary complex, ubiquitination assay, multiple functional genetic tools in single lab\",\n      \"pmids\": [\"29579593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP (GULP1-Keap1 interaction), siRNA knockdown, NRF2 nuclear translocation assay, in vivo xenograft, promoter methylation analysis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for interaction, KD with functional cellular phenotype, in vivo validation; single lab study\",\n      \"pmids\": [\"32817372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic Keap1 knockout in zebrafish and mammalian cells, lysosome quantification, transcriptomic analysis, NRF2 rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined cellular/organismal phenotype, evolutionary conservation across models\",\n      \"pmids\": [\"37216554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"miRNA target reporter assay (3'-UTR luciferase), qRT-PCR, Nrf2 nuclear localization imaging, siRNA and miRNA mimic transfection\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR targeting confirmed, multiple functional readouts; single lab study\",\n      \"pmids\": [\"26453926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-Cas9 gene deletion screens, ROS measurement, metabolic assays, pharmacological inhibitor studies\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-scale CRISPR screen with mechanistic follow-up (ROS assay, metabolic analysis); single study\",\n      \"pmids\": [\"28145866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical methylation assays (PRMT5-KEAP1), co-IP, functional ferroptosis assays, genetic knockdown\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical methylation shown with functional consequences; single lab study\",\n      \"pmids\": [\"37380368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP (DDRGK1-KEAP1 interaction), ubiquitination assay, CRISPR-Cas9 knockout, in vivo xenograft\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with genetic KO validation in vivo; single lab study\",\n      \"pmids\": [\"36965071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"PROTAC/bivalent degrader synthesis, cell-based protein degradation assays, E3 ligase recruitment biochemistry\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based degradation assays with multiple targets; single focused mechanistic study\",\n      \"pmids\": [\"36070758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"S-sulfhydration assay (modified biotin-switch), Nrf2 nuclear translocation imaging, cardiac-specific CSE knockout mouse model, functional ferroptosis assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM (S-sulfhydration) biochemically detected, genetic KO/rescue model, multiple functional readouts; single lab\",\n      \"pmids\": [\"38359744\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KEAP1 is a homodimeric, cysteine-rich substrate adaptor for a CUL3-RBX1 E3 ubiquitin ligase that constitutively ubiquitinates and targets NRF2 for proteasomal degradation under basal conditions; oxidative, electrophilic, or metabolic stress covalently modifies critical sensor cysteines (principally Cys151, Cys273, Cys288) on KEAP1—via alkylation, S-sulfhydration, methylglyoxal-derived crosslinking, or other modifications—causing conformational changes that impair Nrf2 ubiquitination, allowing newly synthesized NRF2 to accumulate, translocate to the nucleus, and activate cytoprotective gene transcription; KEAP1 also targets additional substrates including PGAM5 and regulates ER-phagy via PINK1-directed ubiquitylation of Rtnl1, while its activity is further modulated by competitive binding of proteins such as phospho-p62, GULP1, and DDRGK1, by CMA-mediated lysosomal degradation of KEAP1 itself, and by post-translational modifications including PRMT5-mediated methylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#1, #0]. 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 [#5]. 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 [#2]. Diverse modifiers converge on these cysteines, including the macrophage metabolite itaconate [#6], methylglyoxal-derived methylimidazole crosslinks generated upon PGK1 inhibition [#7], the electrophile curcumin [#8], and hydrogen sulfide via S-sulfhydration [#21], 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 [#13] and, downstream of PINK1, the ER-phagy receptor Rtnl1 to direct selective ER clearance [#12]. KEAP1 activity is further tuned by competitive binding partners—phosphorylated p62 whose KEAP1 affinity is enhanced by mTORC1 and NBR1-driven droplet formation [#4, #10], GULP1 [#14], and DDRGK1 [#19]—by chaperone-mediated autophagy of KEAP1 itself [#11], and by PRMT5-mediated methylation [#18]. Loss of KEAP1 drives constitutive NRF2 signaling with consequences for lysosomal biogenesis [#15] and for the response to targeted kinase inhibitors in lung cancer [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that the human KEAP1 homolog physically sequesters NRF2 in the cytoplasm and that this interaction is redox-sensitive, defining the core regulatory relationship.\",\n      \"evidence\": \"Reciprocal co-IP, immunofluorescence, and GCLC reporter assays with redox perturbation in cells\",\n      \"pmids\": [\"11909699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the enzymatic mechanism by which KEAP1 controls NRF2 levels\", \"No molecular identification of the redox-sensing residues\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro ubiquitination assays, proteasome inhibition, and keap1-knockout mice\",\n      \"pmids\": [\"15706085\", \"15519281\", \"17145701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not pinpoint which cysteines act as the stress sensor\", \"Structural basis of NRF2 presentation unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Site-directed mutagenesis with functional readout supported by proteomic analysis\",\n      \"pmids\": [\"19560482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether different inducers preferentially target different cysteines\", \"Conformational changes not directly visualized\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Kinase phosphorylation assays, mutagenesis, nuclear fractionation, and co-IP\",\n      \"pmids\": [\"19666107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Some cascade steps inferred from indirect evidence\", \"Relative contribution of cysteine versus phosphorylation arms not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"FRET and multiphoton FLIM imaging of KEAP1-NRF2 in single living cells\",\n      \"pmids\": [\"24681086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single advanced-imaging approach from one lab\", \"Does not directly link dynamics to ubiquitin transfer kinetics\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography and protein-protein interaction studies\",\n      \"pmids\": [\"26057936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Static structures do not capture the inducer-triggered conformational transition directly\", \"Structures of modified-cysteine states not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected selective autophagy to NRF2 activation by showing mTORC1-phosphorylated p62 competitively sequesters KEAP1, defining a non-canonical activation route.\",\n      \"evidence\": \"Co-IP, phosphorylation mapping, mTORC1-dependent and genetic deletion/rescue assays\",\n      \"pmids\": [\"24011591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish in vivo physiological triggers of this branch\", \"Stoichiometry of competition with NRF2 unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that endogenous and metabolic electrophiles directly modify KEAP1 cysteines—itaconate alkylation and methylglyoxal-derived crosslinking—linking immunometabolism and glycolysis to NRF2 activation.\",\n      \"evidence\": \"Mass spectrometry covalent mapping, crosslinking assays, genetic KO macrophages and inhibitor studies with NRF2 reporters\",\n      \"pmids\": [\"29590092\", \"30323285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which physiological conditions dominate in vivo\", \"Quantitative thresholds for activation per modification unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded the KEAP1 substrate repertoire beyond NRF2 by showing AMPK-associated KEAP1 ubiquitinates PGAM5 to protect against necroptosis.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, AMPK genetic constructs, and Langendorff heart perfusion\",\n      \"pmids\": [\"29579593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus complex-mediated ubiquitin transfer to PGAM5 not fully separated\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified competitive cytoplasmic partners (GULP1, NBR1) that modulate KEAP1-NRF2 sequestration, with disease relevance to chemoresistance.\",\n      \"evidence\": \"Co-IP, siRNA/KO, live-cell droplet imaging, NRF2 translocation and xenograft assays\",\n      \"pmids\": [\"32817372\", \"31916398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation of some interactions limited\", \"Generality across cell types untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed curcumin as a Cys151-directed electrophilic modifier that stabilizes NRF2 by inhibiting KEAP1-mediated ubiquitination.\",\n      \"evidence\": \"MS, C151S mutagenesis, ubiquitination and reporter assays\",\n      \"pmids\": [\"31972171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity for Cys151 over other cysteines not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed feedback control of KEAP1 abundance itself, showing chaperone-mediated autophagy degrades KEAP1 to amplify NRF2 signaling in a feed-forward loop.\",\n      \"evidence\": \"CMA activation/inhibition, lysosomal fractionation, siRNA, and NRF2 translocation imaging\",\n      \"pmids\": [\"35535673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recognition motif on KEAP1 for CMA not defined\", \"Physiological triggers of CMA-mediated KEAP1 turnover unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated KEAP1 can be repurposed as an E3 ligase for targeted protein degradation, while revealing a narrow target scope and propensity for self-degradation.\",\n      \"evidence\": \"Bivalent degrader synthesis and cell-based degradation assays against BET proteins and FAK\",\n      \"pmids\": [\"36070758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of narrow target scope unresolved\", \"Determinants of KEAP1 self-degradation undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed KEAP1 in organelle quality control by showing PINK1-directed, KEAP1-CUL3-dependent ubiquitylation of Rtnl1 drives ER-phagy, balanced against Parkin-mediated mitophagy.\",\n      \"evidence\": \"Drosophila genetic epistasis, ubiquitylation assays, and confocal localization imaging\",\n      \"pmids\": [\"37633267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PINK1 control over KEAP1 localization not fully defined\", \"Conservation of Rtnl1 substrate role in mammals untested here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified additional KEAP1 regulators—DDRGK1 competitive binding and PRMT5 methylation—that tune NRF2 ubiquitination, ferroptosis resistance, and iron metabolism.\",\n      \"evidence\": \"Co-IP, ubiquitination/methylation assays, CRISPR KO, and ferroptosis/xenograft assays\",\n      \"pmids\": [\"36965071\", \"37380368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Methylation site(s) on KEAP1 not pinpointed\", \"Interplay with cysteine sensing not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended KEAP1-NRF2 function beyond antioxidant defense by showing KEAP1 loss activates TFEB/TFE3-dependent lysosomal biogenesis in a conserved manner.\",\n      \"evidence\": \"Genetic KEAP1 knockout in zebrafish and mammalian cells with transcriptomics and NRF2 rescue\",\n      \"pmids\": [\"37216554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between NRF2 and TFEB/TFE3 not defined\", \"Whether KEAP1 acts on lysosomal regulators directly unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model integrating the diverse KEAP1 modifications\", \"Determinants of substrate choice between NRF2, PGAM5, and Rtnl1 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 13, 12]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2, 6, 7, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 5, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 11, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13, 18, 21]}\n    ],\n    \"complexes\": [\n      \"KEAP1-CUL3-RBX1 E3 ubiquitin ligase\",\n      \"KEAP1-PGAM5-AMPK complex\"\n    ],\n    \"partners\": [\n      \"NFE2L2\",\n      \"CUL3\",\n      \"SQSTM1\",\n      \"PGAM5\",\n      \"GULP1\",\n      \"DDRGK1\",\n      \"NBR1\",\n      \"PRMT5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}