Affinage

NCOA4

Nuclear receptor coactivator 4 · UniProt Q13772

Length
614 aa
Mass
69.7 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NCOA4 is the selective autophagy cargo receptor for ferritin (ferritinophagy), coupling intracellular iron status to lysosomal ferritin turnover and thereby governing the cellular labile iron pool (PMID:24695223). It binds ferritin heavy chain (FTH1) directly through a C-terminal element that recognizes a key surface arginine on FTH1, while associating with ATG8 proteins to deliver ferritin to lysosomes; this interaction is required for ferritin degradation and iron release (PMID:24695223, PMID:26436293, PMID:28754384). NCOA4 homodimerizes and engages FTH1 multivalently to drive phase separation of ferritin into liquid-like condensates that are engulfed by autophagosomes and endosomes via TAX1BP1 (PMID:36066504, PMID:35318808). Iron sensing is intrinsic to the protein: its C-terminal FTH1-binding domain carries a [3Fe-4S] cluster, and holo-NCOA4 is recognized by the HERC2 ubiquitin ligase for proteasomal degradation under iron repletion, whereas apo-NCOA4 binds FTH1 to promote ferritinophagy under iron depletion (PMID:38159858). NCOA4 abundance and activity are further tuned by ATM-mediated phosphorylation (PMID:36752571), additional E3 ligases and a deubiquitylase (TRIM7, DTX2, USP2) (PMID:36067704, PMID:39366066, PMID:38744953), and transcriptional/translational inputs (PMID:36907253, PMID:36940731, PMID:36660932). Through this iron-release function, NCOA4 is essential for systemic, macrophage, and erythroid iron homeostasis and supports heme and hemoglobin synthesis via a PCBP1-ferritin-NCOA4 vectorial iron-transfer axis (PMID:26776506, PMID:28375153, PMID:30630985, PMID:32107334), and it is a principal determinant of ferroptosis sensitivity by controlling labile iron (PMID:36752571, PMID:36067704, PMID:34235259). Independently of iron release, NCOA4 interacts with MCM7 and restrains CMG helicase-mediated DNA replication origin activation, linking iron bioavailability to genome stability (PMID:24910095, PMID:35977492). In its original nuclear-receptor context, NCOA4 (ARA70) acts as a ligand-dependent coactivator of the androgen receptor through an FXXLF motif and of PPARgamma through an LXXLL motif, bridging receptors to the basal transcription machinery, and cooperates with TRbeta during erythroid differentiation (PMID:28864529, PMID:8643607, PMID:15166229).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2014 High

    Established NCOA4's defining function by identifying it as the selective cargo receptor that targets ferritin to lysosomes, answering how cells mobilize stored iron through autophagy.

    Evidence Quantitative autophagosome proteomics with reciprocal Co-IP of NCOA4 and ferritin subunits and knockdown/knockout ferritin-degradation readouts

    PMID:24695223

    Open questions at the time
    • Did not define the molecular interaction interface
    • Did not explain how iron status switches the receptor on or off
  2. 2015 High

    Defined the NCOA4-FTH1 binding interface and revealed iron-dependent HERC2 ubiquitination as the off-switch, showing how ferritinophagy is suppressed under iron excess.

    Evidence Mutagenesis of the FTH1/NCOA4 interface, Co-IP, depletion-reconstitution, ubiquitination assays, and zebrafish genetics

    PMID:26436293

    Open questions at the time
    • Molecular nature of the iron signal sensed by NCOA4 not yet identified
    • Structural basis of HERC2 recognition unresolved
  3. 2016 High

    Demonstrated NCOA4 is essential for systemic iron homeostasis in vivo and mapped the ferritin-targeting activity to the C-terminal domain (aa 239-614).

    Evidence Knockout mouse with dietary iron manipulation plus domain reconstitution in null MEFs

    PMID:26776506

    Open questions at the time
    • Cell-type-specific contributions not dissected
    • Did not resolve erythroid versus systemic mechanisms
  4. 2017 High

    Showed ferritinophagy feeds iron into heme synthesis during erythropoiesis and works in series with PCBP1 to achieve vectorial iron transfer through ferritin.

    Evidence siRNA depletion in an erythroid differentiation model and Pcbp1-KO mouse ex vivo erythroid differentiation with heme/hemoglobin assays

    PMID:28375153

    Open questions at the time
    • Stoichiometry and kinetics of PCBP1-NCOA4 coordination not quantified
    • Mechanism of iron delivery to mitochondria unresolved
  5. 2017 High

    Placed NCOA4 in the nuclear-receptor pathway during erythropoiesis as a TH/TRbeta coactivator recruited to chromatin near terminal differentiation genes.

    Evidence RNA-seq, NCOA4 ChIP-seq, and Ncoa4-KO mouse with TH/TRbeta agonist challenge

    PMID:28864529

    Open questions at the time
    • Relationship between nuclear coactivator and cytoplasmic ferritinophagy roles not integrated
    • Direct DNA/chromatin targets incompletely mapped
  6. 2020 High

    Quantified the NCOA4-ferritin interaction thermodynamically and showed NCOA4 binding itself blocks chemical iron mobilization from the ferritin shell.

    Evidence Isothermal titration calorimetry and in vitro iron oxidation/mobilization kinetics with recombinant NCOA4(383-522)

    PMID:28754384 PMID:32608971

    Open questions at the time
    • In vitro reconstitution may not capture cellular condensate context
    • Physiological consequence of mobilization inhibition unclear
  7. 2022 High

    Reframed ferritinophagy as condensate-driven, showing NCOA4 homodimerization and multivalent FTH1 binding nucleate ferritin condensates captured by autophagosomes and endosomes via TAX1BP1.

    Evidence Live-cell imaging, 3D correlative light-electron microscopy, and dimerization/FTH1-interaction mutants

    PMID:35318808 PMID:36066504

    Open questions at the time
    • How iron status toggles condensate composition not fully resolved
    • Selection between macro- and micro-ferritinophagy routes incompletely defined
  8. 2022 High

    Uncovered an iron-independent function: NCOA4 binds MCM7 and restrains replication origin firing, linking iron bioavailability to controlled DNA replication and genome stability.

    Evidence Xenopus egg-extract depletion-reconstitution, Co-IP with MCM7, and NCOA4-KO MEFs with DNA fiber and replication-stress readouts

    PMID:24910095 PMID:35977492

    Open questions at the time
    • Structural basis of MCM7/CMG inhibition unknown
    • How this nuclear role coordinates with cytoplasmic ferritinophagy unresolved
  9. 2022 High

    Showed NCOA4-driven ferritinophagy sustains iron-sulfur cluster protein synthesis and mitochondrial homeostasis to fuel pancreatic cancer progression, identifying it as a tumor dependency.

    Evidence Patient-derived and murine PDAC models with quantitative proteomics and genetic NCOA4 targeting

    PMID:35771492

    Open questions at the time
    • Generality across tumor types not established here
    • Mechanism coupling ferritinophagy to Fe-S cluster supply not detailed
  10. 2023 High

    Identified the molecular iron sensor: a [3Fe-4S] cluster in the C-terminal domain determines whether NCOA4 is degraded by HERC2 (holo) or binds FTH1 to promote ferritinophagy (apo).

    Evidence In vitro Fe-S cluster reconstitution, mass spectrometry, and differential Co-IP of holo versus apo-NCOA4 with HERC2/FTH1

    PMID:38159858

    Open questions at the time
    • In vivo confirmation of the cluster's regulatory role lacking
    • Cluster assembly/disassembly machinery not identified
  11. 2023 Medium

    Layered additional regulation onto NCOA4 stability and activity through ATM phosphorylation, oxygen tension, and pathogen-driven TRIM21/HERC2 signaling, tuning ferritinophagy and ferroptosis.

    Evidence ATM inhibition/KO with phospho and ferroptosis assays; hypoxia chamber and Fe-S/HERC2 analyses; macrophage Mtb infection with myeloid-specific Ncoa4 KO mice

    PMID:36752571 PMID:37059186 PMID:37066876

    Open questions at the time
    • ATM phosphosites on NCOA4 not mapped
    • Oxygen and infection inputs studied in single labs
  12. 2024 Medium

    Resolved a regulatory network of E3 ligases, a deubiquitylase, transcription factors, an RNA-binding protein, and competitive binders that set NCOA4 levels and thereby ferroptosis sensitivity across disease contexts.

    Evidence Co-IP and K48-ubiquitination assays (TRIM7, DTX2, USP2); promoter/ChIP and reporter analyses (JNK-JUN, STAT3, FOXO1, PTBP1); competitive-binding Co-IP (JWA/ARL6IP5, LCN2, CRY1) with cellular and mouse models

    PMID:36067704 PMID:36660932 PMID:36907253 PMID:36940731 PMID:38522484 PMID:38744191 PMID:38744953 PMID:39206719 PMID:39366066 PMID:39613734

    Open questions at the time
    • Most regulators validated in single labs and disease-specific contexts
    • Hierarchy and interplay among these regulators not integrated
  13. 2024 Medium

    Revealed a non-receptor extracellular role: secreted NCOA4 acts as a danger-associated molecular pattern activating NF-kB via AGER, expanding its function beyond intracellular iron handling.

    Evidence ATG5/MCOLN1 depletion, lysosomal exocytosis assays, AGER-KO macrophages, and endotoxemia/CLP mouse models with neutralizing antibody

    PMID:38916095

    Open questions at the time
    • Single-lab finding awaiting independent confirmation
    • Relationship of secreted NCOA4 to its iron-handling pool unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NCOA4's distinct activities—ferritinophagy, MCM7-dependent replication control, and nuclear-receptor coactivation—are coordinated within a single cell, and how the [3Fe-4S] iron sensor is loaded and unloaded in vivo, remain unresolved.
  • No unified model linking cytoplasmic, nuclear, and secreted functions
  • No structural model of NCOA4 in any of its complexes
  • In vivo Fe-S cluster cycling machinery unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0038024 cargo receptor activity 3 GO:0060090 molecular adaptor activity 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005634 nucleus 3 GO:0005764 lysosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-69306 DNA Replication 1
Partners
ARFTH1HERC2MCM7PPARGTAX1BP1TRIM7USP2

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 NCOA4 was identified as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy): it associates with ATG8 proteins, binds ferritin heavy and light chains, and is required for delivery of ferritin to lysosomes. NCOA4-deficient cells cannot degrade ferritin, leading to decreased bioavailable intracellular iron. Quantitative autophagosome proteomics, co-immunoprecipitation of NCOA4 with ferritin subunits, NCOA4 knockdown/knockout with ferritin degradation and iron bioavailability readouts Nature High 24695223
2015 Direct physical interaction between NCOA4 and FTH1 requires a key surface arginine in FTH1 and a C-terminal element in NCOA4, and is necessary for ferritin delivery to lysosomes via autophagosomes. NCOA4 protein abundance is dually controlled by autophagy and the ubiquitin-proteasome system; under excess iron, HERC2 ubiquitin ligase binds NCOA4 in an iron-dependent manner and promotes its proteasomal degradation, thereby suppressing ferritinophagy. Mutagenesis of FTH1 and NCOA4 interaction interface, Co-IP, depletion-reconstitution, ubiquitination assays, zebrafish genetic model eLife High 26436293
2016 NCOA4 knockout mice show iron accumulation in liver and spleen, elevated transferrin saturation and serum ferritin, and mild microcytic hypochromic anemia; under iron-deprivation or iron-enriched diets, phenotypes are dramatically exacerbated, establishing NCOA4 as essential for systemic iron homeostasis in vivo. Expression of the NCOA4 C-terminal domain (aa 239–614) restores impaired autophagic ferritin targeting in null MEFs. Knockout mouse model, dietary iron manipulation, primary MEF ferritin degradation assay, domain reconstitution Cell reports High 26776506
2017 In developing erythroid cells, NCOA4-mediated ferritinophagy is required for iron flux through ferritin to mitochondria for heme synthesis; NCOA4 depletion impairs iron trafficking through ferritin, reducing heme synthesis and hemoglobin formation. PCBP1 loads iron into ferritin while NCOA4 mediates autophagic release, coordinating vectorial iron transfer. siRNA depletion of NCOA4 and PCBP1 in cultured erythroid differentiation model, Pcbp1-KO mouse ex vivo erythroid differentiation, heme/hemoglobin assays The Journal of clinical investigation High 28375153
2017 The ferritin-binding domain of NCOA4 (residues 383–522) forms a soluble dimer with low secondary structure, binds H-ferritin (FTH1) with nM affinity but not the R23A FTH1 mutant or L-ferritin, and Fe(II) partially inhibits this binding. Each ferritin shell can bind up to 24 NCOA4 fragments, forming highly stable and insoluble complexes. Recombinant expression of NCOA4(383-522) in E. coli, electrophoretic mobility shift assay, ELISA binding assay, CD spectroscopy, metal-ion competition Biochimica et biophysica acta. General subjects High 28754384
2019 Ncoa4 has both cell-autonomous (erythroid) and non-cell-autonomous (macrophage/systemic) roles in erythropoiesis. Acute systemic Ncoa4 KO causes tissue ferritin/iron accumulation and anemia; erythroid-specific KO produces postnatal anemia and hypochromic microcytic anemia; macrophage ferritinophagy is a major route for iron release supporting erythropoiesis, especially under iron deficiency. Inducible systemic KO mouse model, erythroid-specific conditional KO, bone marrow transplantation, hematological and iron parameter readouts Haematologica High 30630985
2020 Using isothermal titration calorimetry, NCOA4(383-522) binds H-rich ferritins with Kd ~0.4 µM (homopolymer) and ~2 µM (heteropolymer), with ~8 NCOA4 molecules per ferritin shell; binding is enthalpically and entropically favored. NCOA4 binding inhibits iron mobilization from ferritin by reducing agents (FMN/NADH, sodium dithionite) in a concentration-dependent manner, suggesting interference with electron transfer through the ferritin shell. Isothermal titration calorimetry, iron oxidation/mobilization kinetic assays in vitro with recombinant proteins Biochemistry High 32608971
2021 Macrophage-specific NCOA4-mediated ferritinophagy is a major route for iron release to support systemic erythropoiesis; Ncoa4-KO bone marrow transplants into wild-type recipients reveal iron retention in spleen macrophages and failure to mobilize iron stores in response to erythropoietin. Reciprocal bone marrow transplantation in Ncoa4-KO mice, iron deficiency diet, erythropoietin challenge, hematological readouts Haematologica High 32107334
2021 NCOA4 drives phase separation/liquid-like condensate formation of ferritin particles via homodimerization of NCOA4 and multivalent FTH1–NCOA4 interactions; these condensates are directly engulfed by autophagosomes and endosomes (macroferritinophagy and microferritinophagy). Disruption of NCOA4 homodimerization or FTH1-binding interface impairs both condensate formation and ferritin degradation. TAX1BP1 is required for condensate incorporation into autophagosomes/endosomes but not for condensate formation. Live-cell imaging, 3D correlative light-electron microscopy, NCOA4 dimerization and FTH1-interaction mutants, autophagy/endosome incorporation assays The Journal of cell biology High 36066504
2022 Under iron repletion, NCOA4 binds Fe3+ through its intrinsically disordered region, forming insoluble condensates that sequester NCOA4 away from ferritin and allow ferritin accumulation. Under prolonged iron repletion, NCOA4 condensates deliver ferritin to lysosomes via a TAX1BP1-dependent non-canonical autophagy pathway, preventing iron deficiency from excessive ferritin storage. Biochemical fractionation, ferritin-NCOA4 condensate imaging, iron chelation/repletion experiments, TAX1BP1 genetic depletion EMBO reports High 35318808
2022 NCOA4 links iron bioavailability to DNA replication: it physically interacts with MCM7 and inhibits CMG helicase-mediated DNA replication origin activation. NCOA4-null MEFs show unscheduled origin activation, reduced inter-origin distance, fork stalling, reduced fork speed, and premature senescence. In iron-depleted cells, NCOA4 knockdown leads to unscheduled DNA synthesis, replication stress, and genome instability. Xenopus laevis egg extract depletion-reconstitution, Co-IP with MCM7, NCOA4-KO MEFs with replication stress readouts, DNA fiber assay, iron depletion experiments Cell reports High 24910095 35977492
2023 The C-terminal FTH1-binding domain of NCOA4 harbors a [3Fe-4S] iron-sulfur cluster (approximately one per monomer). Under iron-repletion, holo-NCOA4 (with [3Fe-4S]) is recognized by HERC2 ubiquitin ligase for polyubiquitination and proteasomal degradation, favoring ferritin iron storage. Under iron-depletion, apo-NCOA4 (lacking the cluster) binds FTH1 to promote ferritinophagy and iron release. Fe-S cluster reconstitution in vitro, mass spectrometry, Co-IP with HERC2 and FTH1 for holo vs. apo-NCOA4, iron depletion/repletion assays The Journal of biological chemistry High 38159858
2023 Cellular oxygen tension regulates NCOA4 iron sensing: under normoxia, NCOA4 forms Fe3+-binding condensates and degrades ferritin; under hypoxia, the Fe-S cluster-mediated HERC2 recognition and proteasomal degradation of NCOA4 is enhanced, reducing ferritinophagy. Both pathways can co-occur in the same cell, with oxygen determining pathway selection. Iron chelation, hypoxia chamber experiments, Fe-S cluster analysis, HERC2 interaction under varying O2 tensions The Journal of biological chemistry Medium 37059186
2023 ATM kinase phosphorylates NCOA4, facilitating NCOA4–ferritin interaction and sustaining ferritinophagy for labile iron release. ATM inhibition or knockout reduces ferritinophagy and confers resistance to ferroptosis in a TRP53-independent manner. ATM pharmacological inhibition and genetic knockout, phosphorylation assays, NCOA4-ferritin Co-IP, ferroptosis assays in MEFs Autophagy Medium 36752571
2023 TRIM21 promotes HERC2 proteasomal degradation downstream of Mtb-activated p38/AKT1 signaling, increasing NCOA4 levels and NCOA4-mediated ferritin degradation in macrophages. This enhances bioavailable iron for intracellular Mtb growth. NCOA4 deficiency in myeloid cells accelerates Mtb clearance in mice. Macrophage infection models, mass spectrometry, genetic depletion of NCOA4/TRIM21/HERC2, myeloid-specific Ncoa4 KO mice The Journal of clinical investigation High 37066876
2023 STING interacts directly with NCOA4 via specific residues (Q237, E316, S322 in the CBD domain of STING and the coiled-coil domain of NCOA4). This interaction triggers ferritinophagy-mediated ferroptosis, stabilizes STING dimers enhancing inflammatory signaling, and reduces nuclear localization of NCOA4, impairing its transcriptional coregulator function. Single-cell RNA-seq, mass spectrometry, Co-IP mapping interaction domains, STING/NCOA4 genetic manipulation, nuclear fractionation Cell death & disease Medium 35902564
2022 TRIM7 E3 ubiquitin ligase directly binds NCOA4 and ubiquitinates it via K48-linked chains, promoting NCOA4 degradation and thereby reducing NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells. Co-IP, ubiquitination assay with K48-linkage characterization, TRIM7 KD/OE with ferritinophagy and ferroptosis readouts Redox biology Medium 36067704
2024 DTX2 E3 ubiquitin ligase binds NCOA4 and promotes its ubiquitination and degradation via K48-linked chains, suppressing NCOA4-mediated ferritinophagy and conferring ferroptosis resistance in NSCLC cells. Co-IP, ubiquitination assay with K48 chain characterization, DTX2 KD/OE with NCOA4 and ferritinophagy readouts Drug resistance updates Medium 39366066
2024 USP2 deubiquitylase stabilizes NCOA4 by removing K48-linked ubiquitin chains; USP2 binds NCOA4 and prevents its degradation, triggering ferritinophagy and ferroptosis in esophageal squamous cell carcinoma. Hypoxia downregulates USP2, thereby decreasing NCOA4 stability and reducing ferritinophagy-mediated ferroptosis. Co-IP, ubiquitin chain type analysis, USP2 KO/OE in vitro and in vivo xenograft, NCOA4 stability assay Oncogene Medium 38744953
2024 FOXO1 transcription factor directly suppresses NCOA4 expression; knockdown of FOXO1 amplifies NCOA4-mediated ferritinophagy and ferroptosis in cochlear spiral ganglion neurons. Disrupting FOXO1–NCOA4 interaction in NCOA4 knockout mice prevents cisplatin-induced ferroptosis. FOXO1 KD and genetic interaction with NCOA4 KO, cisplatin model, luciferase reporter assay implied by 'directly suppress', hearing loss readouts Advanced science Medium 39206719
2024 JWA (ARL6IP5) interacts with NCOA4 at its ferritin binding site, competing with FTH1 binding and thereby inhibiting NCOA4-mediated ferritinophagy and ferroptosis in dopaminergic neurons. Molecular docking, co-immunoprecipitation, and immunofluorescence confirm direct interaction. Molecular docking, Co-IP, immunofluorescence, JWA genetic manipulation in cellular and mouse PD models Redox biology Medium 38744191
2024 Lipocalin-2 (LCN2) interacts with NCOA4 under high-phosphate conditions, potentially accelerating FTH1 degradation via ferritinophagy-dependent ferroptosis in vascular smooth muscle cells, contributing to vascular calcification in CKD. LCN2 KO mice, Co-IP between LCN2 and NCOA4, LCN2 OE in vascular smooth muscle cells with ferritinophagy and ferroptosis readouts Cell death & disease Medium 39613734
2024 Cryptochrome 1 (CRY1) regulates NCOA4 protein stability by promoting HERC2-mediated ubiquitination and degradation of NCOA4; CRY1 knockdown increases NCOA4-mediated ferritinophagy and causes granulosa cell senescence. KL201 (CRY1 stabilizer) reduces ferritinophagy and improves ovarian function in aged mice. Co-IP, ubiquitination assay, NCOA4 siRNA rescue, CRY1 KD/OE, CRY1-stabilizer in vivo Free radical biology & medicine Medium 38522484
2023 JNK-JUN signaling directly upregulates NCOA4 transcription; JUN binds the Ncoa4 promoter and initiates its transcription. Elevated NCOA4 then increases autophagic ferritin degradation and iron levels, causing chondrocyte ferroptosis and osteoarthritis progression. Promoter ChIP of JUN at Ncoa4, JNK/JUN inhibitor experiments, NCOA4 OE/KD in chondrocytes and mouse intra-articular AAV9 delivery Free radical biology & medicine Medium 36907253
2023 IL-6/STAT3 signaling upregulates NCOA4 protein levels; STAT3 inhibition or knockdown reduces NCOA4 and protects cardiomyocytes from ferritinophagy-mediated ferroptosis; STAT3 overexpression increases NCOA4 expression and ferroptotic events. STAT3 KD/OE, NCOA4 siRNA, high-fat diet mouse model with cardiac injury readouts Free radical biology & medicine Medium 36940731
2023 PTBP1 RNA-binding protein promotes NCOA4 translation by directly binding to the 5'-UTR of NCOA4 mRNA (shown by pull-down assay and dual-luciferase assay); PTBP1 silencing does not affect NCOA4 mRNA stability but reduces NCOA4 protein and consequently ferritinophagy-mediated ferroptosis in liver cancer cells. RNA pull-down, dual-luciferase reporter assay, cycloheximide chase (stability negative), PTBP1 siRNA with ferroptosis readouts Oncology reports Medium 36660932
2022 NCOA4-mediated ferritinophagy is upregulated in pancreatic ductal adenocarcinoma to sustain iron availability; quantitative proteomics shows that ferritinophagy fuels iron-sulfur cluster protein synthesis to support mitochondrial homeostasis and PDAC tumor progression. NCOA4 targeting leads to tumor growth delay. Patient-derived and murine PDAC models, quantitative proteomics, NCOA4 genetic targeting, iron-sulfur cluster protein analysis Cancer discovery High 35771492
2017 Thyroid hormone receptor beta (TRβ) cooperates with NCOA4 during terminal human erythroid differentiation; genome-wide analysis shows TH promotes NCOA4 recruitment to chromatin regions near Pol II associated with terminal differentiation transcripts. Ncoa4-/- mice are anemic perinatally and fail to respond to TH with enhanced erythropoiesis, placing NCOA4 as a critical coactivator downstream of TH/TRβ in erythropoiesis. RNA-seq in reticulocytes, ChIP-seq for NCOA4 chromatin recruitment, Ncoa4-KO mouse with TH/TRβ agonist challenge, TH depletion culture assay Proceedings of the National Academy of Sciences High 28864529
2021 Compound 9a directly binds to recombinant NCOA4(383-522) and blocks the NCOA4–FTH1 protein-protein interaction, reducing bioavailable intracellular ferrous iron and inhibiting ferroptosis, establishing this domain as a druggable interface. Binding assay with recombinant NCOA4(383-522), NCOA4-FTH1 interaction inhibition assay, cellular ferroptosis assay, in vivo ischemic stroke rat model ACS central science Medium 34235259
1996 ARA70 (NCOA4) was identified as a ligand-dependent coactivator of the androgen receptor (AR) via yeast two-hybrid; it enhances AR transcriptional activity ~10-fold in the presence of androgen but only marginally activates other steroid receptors (ER, GR, PR) in DU145 prostate cancer cells. Yeast two-hybrid, transient transfection reporter assay in DU145 cells Proceedings of the National Academy of Sciences Medium 8643607
1999 ARA70/ELE1alpha interacts in vitro with AR, GR, and ER in a ligand-independent manner via the ligand-binding domain of the receptors and a region corresponding to predicted helix 3 of AR (mutation of L712R greatly reduces AR affinity). ARA70 lacks intrinsic transcription activation domain or histone acetyltransferase activity but interacts with p/CAF histone acetyltransferase and basal transcription factor TFIIB, suggesting a bridging function. In vitro GST pulldown and Co-IP, site-directed mutagenesis of AR L712R, HAT activity assay, reporter assay in DU145/HeLa/COS cells Molecular endocrinology Medium 9892017
1999 ARA70 functions as a ligand-enhanced coactivator for PPARgamma: ARA70 and PPARgamma physically interact by co-immunoprecipitation and mammalian two-hybrid, and cotransfection of AR can squelch PPARgamma-ARA70 transactivation, indicating cross-talk between PPARgamma- and AR-mediated signaling. Co-immunoprecipitation, mammalian two-hybrid, transient transfection reporter assay in DU145 cells, ligand enhancement test The Journal of biological chemistry Medium 10347167
2004 ARA70 promotes AR activity via a FXXLF motif within the ARA70-N2 domain (aa 176-401), not via the LXXLL motif (aa 92-96); the LXXLL motif is required for interaction with other receptors (e.g. PPARgamma). ARA70 enhances AR transactivation by increasing AR protein expression, stability, and nuclear translocation. Domain deletion/mutation analysis, reporter assays, AR expression and stability measurements, nuclear translocation assay The Journal of biological chemistry Medium 15166229
2003 Antiandrogens (hydroxyflutamide, bicalutamide, cyproterone acetate, RU58841), genistein, and RU486 promote interaction between AR and ARA70 in a dose-dependent manner in mammalian two-hybrid assay, and cotransfection of AR with ARA70 significantly enhances AR transcriptional activity in DU145 cells, providing a molecular mechanism for antiandrogen agonist activity. Mammalian two-hybrid assay, chloramphenicol acetyltransferase reporter assay, dose-response experiments in DU145 cells Proceedings of the National Academy of Sciences Medium 9636157
2001 The RFG (NCOA4) coiled-coil domain mediates oligomerization of RET/PTC3, activates its kinase and transforming activity, mediates physical association of RET/PTC3 with endogenous RFG protein (making RFG a substrate for RET/PTC3 kinase), and re-localizes RET/PTC3 to the membrane/particulate cell compartment. Co-IP, kinase autophosphorylation assay, focus-formation transformation assay, subcellular fractionation, coiled-coil domain deletion mutants Oncogene Medium 11313992
2025 Reduced mechanical tension decreases intracellular free iron by enhancing FTH1 expression and diminishing NCOA4, which mediates FTH1 phase separation-induced ferritinophagy. Targeting NCOA4 rescues ferroptosis susceptibility under low mechanical tension through modulation of FTH1 phase separation-driven autophagy. Mechanical tension manipulation, NCOA4 genetic targeting, FTH1 phase separation assay, ferroptosis readouts Autophagy Medium 39988734
2024 Activated macrophages and monocytes secrete NCOA4 via autophagy-dependent lysosomal exocytosis (mediated by ATG5 and MCOLN1), and extracellular NCOA4 acts as a danger-associated molecular pattern that activates NF-κB by promoting NFKBIA degradation in a pattern-recognition receptor AGER-dependent (not TLR4-dependent) manner. ATG5/MCOLN1 genetic depletion, lysosomal exocytosis assay, AGER KO macrophages, endotoxemia/CLP mouse model, anti-NCOA4 neutralizing antibody Autophagy Medium 38916095

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 1684 24695223
1996 Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proceedings of the National Academy of Sciences of the United States of America 511 8643607
2015 Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. eLife 465 26436293
2021 Inhibiting Ferroptosis through Disrupting the NCOA4-FTH1 Interaction: A New Mechanism of Action. ACS central science 427 34235259
2018 The Role of NCOA4-Mediated Ferritinophagy in Health and Disease. Pharmaceuticals (Basel, Switzerland) 325 30360520
1994 Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma. Oncogene 315 8290261
2021 The Role of NCOA4-Mediated Ferritinophagy in Ferroptosis. Advances in experimental medicine and biology 264 34370287
2016 NCOA4 Deficiency Impairs Systemic Iron Homeostasis. Cell reports 202 26776506
1998 The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer research 200 9850089
2019 NCOA4-Mediated Ferritinophagy: A Potential Link to Neurodegeneration. Frontiers in neuroscience 196 30930742
2023 ATM orchestrates ferritinophagy and ferroptosis by phosphorylating NCOA4. Autophagy 195 36752571
2022 NCOA4-mediated ferritinophagy is involved in ionizing radiation-induced ferroptosis of intestinal epithelial cells. Redox biology 195 35932693
1998 Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells. Proceedings of the National Academy of Sciences of the United States of America 173 9636157
2003 PP2C phosphatases Ptc2 and Ptc3 are required for DNA checkpoint inactivation after a double-strand break. Molecular cell 170 12667463
2022 The interaction between STING and NCOA4 exacerbates lethal sepsis by orchestrating ferroptosis and inflammatory responses in macrophages. Cell death & disease 165 35902564
2021 Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines. Oncogene 150 33420375
2017 PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis. The Journal of clinical investigation 144 28375153
2022 NCOA4-Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron-Sulfur Cluster Proteins. Cancer discovery 143 35771492
2022 Melatonin inhibits ferroptosis and delays age-related cataract by regulating SIRT6/p-Nrf2/GPX4 and SIRT6/NCOA4/FTH1 pathways. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 131 36463827
2022 TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells. Redox biology 130 36067704
2022 NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and microferritinophagy. The Journal of cell biology 120 36066504
2023 STAT3 signaling promotes cardiac injury by upregulating NCOA4-mediated ferritinophagy and ferroptosis in high-fat-diet fed mice. Free radical biology & medicine 116 36940731
1999 Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform. Molecular endocrinology (Baltimore, Md.) 113 9892017
1999 Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. The Journal of biological chemistry 111 10347167
2023 JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates osteoarthritis via ferritinophagy. Free radical biology & medicine 108 36907253
1996 Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer. Oncogene 101 8806699
2023 STING promotes ferroptosis through NCOA4-dependent ferritinophagy in acute kidney injury. Free radical biology & medicine 100 37634745
2019 NCOA4-RET and TRIM27-RET Are Characteristic Gene Fusions in Salivary Intraductal Carcinoma, Including Invasive and Metastatic Tumors: Is "Intraductal" Correct? The American journal of surgical pathology 94 31162284
2022 Iron-induced NCOA4 condensation regulates ferritin fate and iron homeostasis. EMBO reports 89 35318808
1999 Chromosomal breakpoint positions suggest a direct role for radiation in inducing illegitimate recombination between the ELE1 and RET genes in radiation-induced thyroid carcinomas. Oncogene 86 10597232
2017 Expression and characterization of the ferritin binding domain of Nuclear Receptor Coactivator-4 (NCOA4). Biochimica et biophysica acta. General subjects 78 28754384
2005 Endogenous coactivator ARA70 interacts with estrogen receptor alpha (ERalpha) and modulates the functional ERalpha/androgen receptor interplay in MCF-7 cells. The Journal of biological chemistry 78 15772083
2022 Caryophyllene Oxide Induces Ferritinophagy by Regulating the NCOA4/FTH1/LC3 Pathway in Hepatocellular Carcinoma. Frontiers in pharmacology 77 35899120
2022 cGAS-STING pathway aggravates early cerebral ischemia-reperfusion injury in mice by activating NCOA4-mediated ferritinophagy. Experimental neurology 73 36343680
2004 Functional domain and motif analyses of androgen receptor coregulator ARA70 and its differential expression in prostate cancer. The Journal of biological chemistry 72 15166229
1994 The two genes generating RET/PTC3 are localized in chromosomal band 10q11.2. Genes, chromosomes & cancer 67 7529046
2021 NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice. Haematologica 66 32107334
2024 Salidroside sensitizes Triple-negative breast cancer to ferroptosis by SCD1-mediated lipogenesis and NCOA4-mediated ferritinophagy. Journal of advanced research 60 39353532
2003 Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors. Oncogene 60 12881713
2024 Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis. Redox biology 57 38335622
2014 NCOA4 transcriptional coactivator inhibits activation of DNA replication origins. Molecular cell 56 24910095
2022 d-Borneol enhances cisplatin sensitivity via autophagy dependent EMT signaling and NCOA4-mediated ferritinophagy. Phytomedicine : international journal of phytotherapy and phytopharmacology 55 36030746
2001 The RFG oligomerization domain mediates kinase activation and re-localization of the RET/PTC3 oncoprotein to the plasma membrane. Oncogene 53 11313992
2019 NCOA4 maintains murine erythropoiesis via cell autonomous and non-autonomous mechanisms. Haematologica 52 30630985
2024 Emodin induces ferroptosis in colorectal cancer through NCOA4-mediated ferritinophagy and NF-κb pathway inactivation. Apoptosis : an international journal on programmed cell death 49 38704789
2023 Defective NCOA4-dependent ferroptosis in senescent fibroblasts retards diabetic wound healing. Cell death discovery 48 37117222
2023 Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth. The Journal of clinical investigation 47 37066876
1999 RFG (ARA70, ELE1) interacts with the human androgen receptor in a ligand-dependent fashion, but functions only weakly as a coactivator in cotransfection assays. Molecular endocrinology (Baltimore, Md.) 47 10517667
2021 NCOA4-mediated ferritinophagy promoted inflammatory responses in periodontitis. Journal of periodontal research 46 33533512
2017 Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation. Proceedings of the National Academy of Sciences of the United States of America 44 28864529
2010 Protein phosphatases pph3, ptc2, and ptc3 play redundant roles in DNA double-strand break repair by homologous recombination. Molecular and cellular biology 44 21135129
2004 Real-time quantitative RT-PCR identifies distinct c-RET, RET/PTC1 and RET/PTC3 expression patterns in papillary thyroid carcinoma. Laboratory investigation; a journal of technical methods and pathology 44 15502856
2006 Activation of the Erk8 mitogen-activated protein (MAP) kinase by RET/PTC3, a constitutively active form of the RET proto-oncogene. The Journal of biological chemistry 43 16484222
2023 Iron derived from NCOA4-mediated ferritinophagy causes cellular senescence via the cGAS-STING pathway. Cell death discovery 42 37980349
2007 Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor co-activator ARA70. The American journal of pathology 42 18156210
2024 NCOA4 linked to endothelial cell ferritinophagy and ferroptosis:a key regulator aggravate aortic endothelial inflammation and atherosclerosis. Redox biology 41 39700692
2001 Loss of androgen receptor associated protein 70 (ARA70) expression in a subset of HER2-positive breast cancers. Breast cancer research and treatment 41 11561770
2024 COPZ1 regulates ferroptosis through NCOA4-mediated ferritinophagy in lung adenocarcinoma. Biochimica et biophysica acta. General subjects 38 39181476
2003 Reducing the agonist activity of antiandrogens by a dominant-negative androgen receptor coregulator ARA70 in prostate cancer cells. The Journal of biological chemistry 37 12649293
2024 E3 ubiquitin ligase DTX2 fosters ferroptosis resistance via suppressing NCOA4-mediated ferritinophagy in non-small cell lung cancer. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 36 39366066
2001 RET rearrangements in radiation-induced papillary thyroid carcinomas: high prevalence of topoisomerase I sites at breakpoints and microhomology-mediated end joining in ELE1 and RET chimeric genes. Genomics 36 11318605
2024 FOXO1-NCOA4 Axis Contributes to Cisplatin-Induced Cochlea Spiral Ganglion Neuron Ferroptosis via Ferritinophagy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 35 39206719
2023 NCOA4 requires a [3Fe-4S] to sense and maintain the iron homeostasis. The Journal of biological chemistry 35 38159858
2022 NCOA4 links iron bioavailability to DNA metabolism. Cell reports 33 35977492
2023 2D MoS2 Nanosheets Induce Ferroptosis by Promoting NCOA4-Dependent Ferritinophagy and Inhibiting Ferroportin. Small (Weinheim an der Bergstrasse, Germany) 32 36908089
2001 Activation of androgen receptor-associated protein 70 (ARA70) mRNA expression in ovarian cancer. Gynecologic oncology 32 11161850
2024 Selenium nanoparticles alleviate renal ischemia/reperfusion injury by inhibiting ferritinophagy via the XBP1/NCOA4 pathway. Cell communication and signaling : CCS 31 39061070
2023 Oxygen modulates iron homeostasis by switching iron sensing of NCOA4. The Journal of biological chemistry 30 37059186
2023 The PTBP1‑NCOA4 axis promotes ferroptosis in liver cancer cells. Oncology reports 28 36660932
2024 Regulation of NCOA4-mediated iron recycling ameliorates paraquat-induced lung injury by inhibiting ferroptosis. Cell communication and signaling : CCS 27 38388414
2021 Dexmedetomidine reverses MTX-induced neurotoxicity and inflammation in hippocampal HT22 cell lines via NCOA4-mediated ferritinophagy. Aging 27 33632938
2020 Thermodynamic and Kinetic Studies of the Interaction of Nuclear Receptor Coactivator-4 (NCOA4) with Human Ferritin. Biochemistry 27 32608971
2024 Ginsenoside Rg5 inhibits glioblastoma by activating ferroptosis via NR3C1/HSPB1/NCOA4. Phytomedicine : international journal of phytotherapy and phytopharmacology 25 38640858
2023 Inhibitory Effects of Esculetin on Liver Cancer Through Triggering NCOA4 Pathway-Mediation Ferritinophagy in vivo and in vitro. Journal of hepatocellular carcinoma 25 37069958
2001 Expression of RFG/ELE1alpha/ARA70 in normal and malignant prostatic epithelial cell cultures and lines: regulation by methylation and sex steroids. Molecular carcinogenesis 25 11255259
1999 Human N-ras, TRK-T1, and RET/PTC3 oncogenes, driven by a thyroglobulin promoter, differently affect the expression of differentiation markers and the proliferation of thyroid epithelial cells. Oncology research 25 10821536
2023 Schisandrin B promotes senescence of activated hepatic stellate cell via NCOA4-mediated ferritinophagy. Pharmaceutical biology 24 37010139
2024 Melatonin alleviates septic ARDS by inhibiting NCOA4-mediated ferritinophagy in alveolar macrophages. Cell death discovery 22 38789436
2010 The RET/PTC3 oncogene activates classical NF-κB by stabilizing NIK. Oncogene 22 20818435
2024 Extracellular NCOA4 is a mediator of septic death by activating the AGER-NFKB pathway. Autophagy 21 38916095
2024 Lipocalin-2 promotes CKD vascular calcification by aggravating VSMCs ferroptosis through NCOA4/FTH1-mediated ferritinophagy. Cell death & disease 21 39613734
2023 Nrf2 protects against cartilage endplate degeneration through inhibiting NCOA4‑mediated ferritinophagy. International journal of molecular medicine 21 38063237
2024 Cryptochrome 1 regulates ovarian granulosa cell senescence through NCOA4-mediated ferritinophagy. Free radical biology & medicine 20 38522484
2024 NCOA4-mediated ferritinophagy participates in cadmium-triggered ferroptosis in spermatogonia. Toxicology 20 38768701
2010 Variable expression of nuclear receptor coactivator 4 (NcoA4) during mouse embryonic development. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 20 20354146
2005 RET/PTC3 rearrangement and thyroid differentiation gene analysis in a struma ovarii fortuitously revealed by elevated serum thyroglobulin concentration. Thyroid : official journal of the American Thyroid Association 20 16405408
2024 JWA binding to NCOA4 alleviates degeneration in dopaminergic neurons through suppression of ferritinophagy in Parkinson's disease. Redox biology 19 38744191
2016 Signal Transducer and Activator of Transcription 1 Plays a Pivotal Role in RET/PTC3 Oncogene-induced Expression of Indoleamine 2,3-Dioxygenase 1. The Journal of biological chemistry 19 27994058
2005 Expression of androgen receptor coactivator ARA70/ELE1 in androgenic alopecia. Journal of cutaneous pathology 19 16115056
2025 Autophagy induced by mechanical stress sensitizes cells to ferroptosis by NCOA4-FTH1 axis. Autophagy 18 39988734
2024 Alleviated NCOA4-mediated ferritinophagy protected RA FLSs from ferroptosis in lipopolysaccharide-induced inflammation under hypoxia. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 18 38189810
2024 Regulating NCOA4-Mediated Ferritinophagy for Therapeutic Intervention in Cerebral Ischemia-Reperfusion Injury. Neurochemical research 18 38713437
2002 Mutations in the helix 3 region of the androgen receptor abrogate ARA70 promotion of 17beta-estradiol-induced androgen receptor transactivation. The Journal of biological chemistry 18 12068007
2014 Effects of siRNA on RET/PTC3 junction oncogene in papillary thyroid carcinoma: from molecular and cellular studies to preclinical investigations. PloS one 17 24759995
2024 Polyphyllin B inhibited STAT3/NCOA4 pathway and restored gut microbiota to ameliorate lung tissue injury in cigarette smoke-induced mice. BMC biotechnology 16 38459479
2024 Hypoxia inhibits ferritinophagy-mediated ferroptosis in esophageal squamous cell carcinoma via the USP2-NCOA4 axis. Oncogene 16 38744953
2024 Casticin induces ferroptosis in human osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4. Biochemical pharmacology 16 38852641
2022 NCOA4 Regulates Iron Recycling and Responds to Hepcidin Activity and Lipopolysaccharide in Macrophages. Antioxidants (Basel, Switzerland) 16 36290647
2009 High iodine concentration attenuates RET/PTC3 oncogene activation in thyroid follicular cells. Thyroid : official journal of the American Thyroid Association 16 19725779
2006 Myostatin negatively regulates the expression of the steroid receptor co-factor ARA70. Journal of cellular physiology 15 16110473

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