Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Ferritin is a predominantly cytoplasmic protein in mammalian cells. The IBA annotation based on phylogenetic inference is well-supported by the UniProt subcellular location annotation which states "Cytoplasm" with experimental evidence (PMID:26436293). Crystal structures and functional studies consistently show cytoplasmic localization of the ferritin complex. Reason: The cytoplasmic localization of FTH1 is a core functional characteristic. The 24-mer ferritin nanocage forms in the cytoplasm where it performs its iron storage function. This is supported by extensive structural and cell biological evidence. Supporting Evidence: PMID:26436293 NCOA4 is a selective cargo receptor for the autophagic turnover of ferritin, a process critical for regulation of intracellular iron bioavailability file:human/FTH1/FTH1-deep-research-falcon.md model: Edison Scientific Literature
GO:0008198 ferrous iron binding	IBA GO_REF:0000033	ACCEPT	Summary: Ferrous iron (Fe2+) binding is the initial step in ferritin's iron storage mechanism. The IBA annotation is strongly supported by direct experimental evidence from PMID:9003196 which used stopped-flow assays and site-directed mutagenesis to demonstrate Fe2+ binding at the ferroxidase center, showing that "the first 48 Fe(II) atoms/molecule added are bound and oxidized at the dinuclear centers." Reason: Fe2+ binding is essential to FTH1's core ferroxidase function. The ferritin H chain binds Fe2+ at its dinuclear ferroxidase center (sites A and B) prior to oxidation. This is experimentally validated and central to the protein's physiological role. Supporting Evidence: PMID:9003196 the first 48 Fe(II) atoms/molecule added are bound and oxidized at the dinuclear centers
GO:0006826 iron ion transport	IBA GO_REF:0000033	MODIFY	Summary: Iron ion transport describes the movement of iron ions. While FTH1 is involved in iron handling, its primary role is iron storage rather than active transport. The UniProt function annotation states FTH1 "Stores iron in a soluble, non-toxic, readily available form" and "Also plays a role in delivery of iron to cells" but this delivery function is attributed to the assembled ferritin complex being taken up by cells, not direct transport activity. Reason: FTH1's primary function is iron sequestration and storage, not active transport. The term "iron ion transport" implies movement across membranes or between compartments, whereas ferritin accumulates iron within its mineral core. Iron release occurs via ferritinophagy (lysosomal degradation), not a transport mechanism intrinsic to FTH1. Proposed replacements: intracellular iron ion homeostasis
GO:0008199 ferric iron binding	IBA GO_REF:0000033	ACCEPT	Summary: Ferric iron (Fe3+) is the oxidized form stored within the ferritin mineral core. The deep research confirms that FTH1 catalyzes "oxidation of Fe2+ to Fe3+, producing an Fe(III) mineral within the 24-mer lumen." The ferric iron is coordinated in a ferrihydrite-like mineral structure. Reason: Fe3+ binding/storage is the end product of FTH1's ferroxidase activity. The ferrihydrite mineral core contains coordinated Fe3+ ions. This is central to the iron storage function of ferritin. Supporting Evidence: PMID:9003196 The ferroxidase activity of human ferritin has previously been associated with a diiron site situated centrally within the four-helix bundle of H-type chains
GO:0004322 ferroxidase activity	IEA GO_REF:0000120	ACCEPT	Summary: The IEA annotation based on EC number mapping (EC 1.16.3.1) is appropriate. FTH1's ferroxidase activity is well-established experimentally, with the catalytic reaction: 4 Fe(2+) + O2 + 4 H(+) = 4 Fe(3+) + 2 H2O. This is validated by direct experimental evidence in PMID:9003196. Reason: Ferroxidase activity is the defining enzymatic function of the ferritin heavy chain. The dinuclear ferroxidase center in FTH1 oxidizes Fe2+ to Fe3+ coupled to oxygen reduction. This is the mechanistic basis for ferritin's iron storage capacity and distinguishes the H chain from the L chain. Supporting Evidence: PMID:9003196 The ferroxidase activity of human ferritin has previously been associated with a diiron site situated centrally within the four-helix bundle of H-type chains
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Duplicate annotation for cytoplasmic localization with IEA evidence based on UniProtKB subcellular location vocabulary mapping. Consistent with the IBA annotation above. Reason: Cytoplasmic localization is well-supported and a core characteristic. This annotation is redundant with the IBA annotation but correctly captures the primary subcellular location.
GO:0005764 lysosome	IEA GO_REF:0000044	ACCEPT	Summary: Lysosomal localization of ferritin occurs during ferritinophagy. PMID:26436293 demonstrates that ferritin is delivered to lysosomes via NCOA4-mediated autophagy. UniProt subcellular location annotation confirms "Lysosome" with experimental evidence. Reason: Lysosomal targeting is integral to ferritin's physiological turnover and iron release mechanism. NCOA4-mediated ferritinophagy delivers FTH1-containing complexes to lysosomes for degradation, which is essential for iron recycling. Supporting Evidence: PMID:26436293 direct association via a key surface arginine in FTH1 and a C-terminal element in NCOA4 is required for delivery of ferritin to the lysosome via autophagosomes
GO:0005776 autophagosome	IEA GO_REF:0000044	ACCEPT	Summary: Autophagosome localization reflects ferritinophagy, where NCOA4 delivers ferritin to autophagosomes for eventual lysosomal degradation. This is supported by UniProt annotation "Cytoplasmic vesicle, autophagosome" with experimental evidence from PMID:24695223. Reason: Autophagosome localization is part of the ferritinophagy pathway. NCOA4 binds ferritin and traffics the complex to autophagosomes prior to lysosomal fusion. This is physiologically important for regulated iron release. Supporting Evidence: PMID:24695223 delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin led to decreased bioavailable intracellular iron
GO:0006826 iron ion transport	IEA GO_REF:0000002	MODIFY	Summary: Duplicate annotation for iron ion transport from InterPro domain mapping. Same considerations apply as for the IBA annotation. Reason: FTH1's primary function is iron sequestration/storage within the ferritin shell, not active membrane transport. While iron enters and exits the ferritin cage, this is not a transport function in the GO sense. Proposed replacements: intracellular iron ion homeostasis
GO:0006879 intracellular iron ion homeostasis	IEA GO_REF:0000002	ACCEPT	Summary: FTH1 is central to intracellular iron homeostasis through its iron storage function. By sequestering excess iron as inert ferric mineral, FTH1 buffers the labile iron pool and prevents iron-mediated toxicity. This is supported by the deep research review and TAS annotation from PMID:6589621. Reason: Intracellular iron ion homeostasis accurately describes FTH1's physiological role. The ferritin system maintains iron balance by storing excess iron and releasing it when needed through ferritinophagy. Supporting Evidence: PMID:6589621 Ferritin, the main iron-storage protein, is composed of two partially homologous subunits, heavy (H) and light (L)
GO:0008199 ferric iron binding	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate annotation for ferric iron binding from InterPro domain mapping. Same considerations apply as for the IBA annotation. Reason: Fe3+ binding/storage is central to ferritin function. The IEA annotation is consistent with the IBA annotation and well-supported by experimental evidence.
GO:0016491 oxidoreductase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: The oxidoreductase activity annotation is accurate but too general. FTH1 has the more specific ferroxidase activity (GO:0004322) which is already annotated. The general oxidoreductase term does not add informative value. Reason: While technically correct (ferroxidase is an oxidoreductase), this term is too broad to be informative. The specific ferroxidase activity annotation (GO:0004322) provides the functionally relevant information.
GO:0031410 cytoplasmic vesicle	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Cytoplasmic vesicle is a broad term that encompasses autophagosomes. The more specific autophagosome annotation (GO:0005776) is already present. This general annotation is less informative. Reason: The specific autophagosome localization is already captured. "Cytoplasmic vesicle" is too general to be maximally informative when more specific terms are annotated.
GO:0046872 metal ion binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Metal ion binding is extremely general. FTH1 has specific annotations for ferrous and ferric iron binding which are much more informative. This general term does not add value. Reason: FTH1 is specifically an iron-binding protein, not a general metal binder. The specific ferrous iron binding (GO:0008198) and ferric iron binding (GO:0008199) annotations provide the relevant functional information.
GO:0005515 protein binding	IPI PMID:16169070 A human protein-protein interaction network: a resource for ...	MARK AS OVER ANNOTATED	Summary: High-throughput protein-protein interaction data showing interaction with FTL (P02792). The FTH1-FTL interaction is biologically meaningful for ferritin heteropolymer assembly. Reason: While the FTH1-FTL interaction is functionally important for ferritin assembly, "protein binding" is uninformative. The identical protein binding annotation captures homo-oligomerization, but a more specific term for hetero-oligomerization with FTL would be more valuable. Supporting Evidence: PMID:16169070 A human protein-protein interaction network: a resource for annotating the proteome.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: High-throughput PPI data showing interactions with FTL (P02792) and FXR2 (P51116). The FTL interaction is functionally relevant. Reason: Generic protein binding annotation provides minimal functional insight. The FTL interaction reflects ferritin heteropolymer assembly; other interactions require validation for functional relevance. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network.
GO:0005515 protein binding	IPI PMID:17355907 The TSC1 gene product hamartin interacts with NADE.	MARK AS OVER ANNOTATED	Summary: Interaction with TSC1 (Q92574) hamartin reported. The functional significance of this interaction is unclear from available literature. Reason: Generic protein binding annotation. The biological relevance of the FTH1-TSC1 interaction is not well established in the context of ferritin's iron storage function. Supporting Evidence: PMID:17355907 2007 Feb 12. The TSC1 gene product hamartin interacts with NADE.
GO:0005515 protein binding	IPI PMID:20133674 Binding and uptake of H-ferritin are mediated by human trans...	KEEP AS NON CORE	Summary: Interaction with TFRC (P02786, transferrin receptor 1). This interaction is functionally meaningful as TfR1 mediates cellular uptake of extracellular H-ferritin. Reason: The FTH1-TFRC interaction is biologically significant for H-ferritin uptake, but this represents an extracellular signaling/uptake function rather than the core intracellular iron storage function. A more specific MF term would be preferable. Supporting Evidence: PMID:20133674 Binding and uptake of H-ferritin are mediated by human transferrin receptor-1.
GO:0005515 protein binding	IPI PMID:20195357 A comprehensive resource of interacting protein regions for ...	MARK AS OVER ANNOTATED	Summary: Interaction with MAX (P61244) transcription factor. The functional significance of this interaction is unclear. Reason: Generic protein binding annotation from high-throughput study. The biological relevance of the FTH1-MAX interaction is not established. Supporting Evidence: PMID:20195357 A comprehensive resource of interacting protein regions for refining human transcription factor networks.
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	MARK AS OVER ANNOTATED	Summary: Next-generation sequencing interactome study showing FTL interaction. Reason: Redundant with other FTH1-FTL interaction annotations. Generic protein binding is uninformative. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets.
GO:0005515 protein binding	IPI PMID:21573799 FTH1 binds to Daxx and inhibits Daxx-mediated cell apoptosis...	KEEP AS NON CORE	Summary: FTH1 binds DAXX (Q9UER7) and inhibits DAXX-mediated cell apoptosis. This represents a specific functional interaction. Reason: The FTH1-DAXX interaction appears to have functional consequences for apoptosis regulation. However, this represents a secondary/non-core function rather than the primary iron storage role. The generic "protein binding" term is still uninformative - a more specific term would be preferable. Supporting Evidence: PMID:21573799 May 15. FTH1 binds to Daxx and inhibits Daxx-mediated cell apoptosis.
GO:0005515 protein binding	IPI PMID:21653829 Protein interactome reveals converging molecular pathways am...	MARK AS OVER ANNOTATED	Summary: High-throughput study on autism-related protein interactome showing FXR2 and TSC1 interactions. Reason: Generic protein binding from high-throughput study. The biological relevance of these interactions to ferritin function is unclear. Supporting Evidence: PMID:21653829 Protein interactome reveals converging molecular pathways among autism disorders.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: Liver protein interactome study showing DAXX interaction. Reason: Redundant with other DAXX interaction annotation. Generic protein binding is uninformative. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver.
GO:0005515 protein binding	IPI PMID:22458338 Host-pathogen interactome mapping for HTLV-1 and -2 retrovir...	MARK AS OVER ANNOTATED	Summary: Host-pathogen interactome study showing interaction with HTLV HBZ protein (Q2Q067). Reason: Viral protein interaction from host-pathogen study. The biological significance for normal ferritin function is unclear. Generic protein binding is uninformative. Supporting Evidence: PMID:22458338 Host-pathogen interactome mapping for HTLV-1 and -2 retroviruses.
GO:0005515 protein binding	IPI PMID:25277244 The functional landscape of Hsp27 reveals new cellular proce...	MARK AS OVER ANNOTATED	Summary: Interaction with HSPB1/Hsp27 (P04792) from functional landscape study. Reason: The biological significance of the FTH1-HSPB1 interaction is unclear. Generic protein binding annotation is uninformative. Supporting Evidence: PMID:25277244 Epub 2014 Oct 2. The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets.
GO:0005515 protein binding	IPI PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro...	ACCEPT	Summary: Interaction with NCOA4 (Q13772), the cargo receptor that mediates ferritinophagy. This is a critical functional interaction for ferritin turnover. Reason: The FTH1-NCOA4 interaction is functionally essential for ferritinophagy and iron homeostasis. NCOA4 binds FTH1 at Arg-23 to target ferritin to autolysosomes. While "protein binding" is generic, this specific interaction is core to ferritin biology. Supporting Evidence: PMID:25327288 NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Proteome-scale interactome map showing FTL interaction. Reason: Redundant with other FTH1-FTL interaction annotations. Generic protein binding is uninformative. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	MARK AS OVER ANNOTATED	Summary: Study on genetic variant effects on protein interactions, showing FTL interaction. Reason: Redundant FTL interaction annotation. Generic protein binding is uninformative. Supporting Evidence: PMID:25910212 Widespread macromolecular interaction perturbations in human genetic disorders.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Human interactome architecture study showing FTL and NCOA4 interactions. Reason: Redundant with existing annotations. The NCOA4 interaction is accepted elsewhere. Generic protein binding is uninformative. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: Study on genetic variant disruption of protein interactions, showing FTL and FXR2 interactions. Reason: Redundant FTL interaction annotation. Generic protein binding is uninformative. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Reference interactome map showing BAG4 (O95429) interaction. Reason: The biological significance of FTH1-BAG4 interaction is unclear. Generic protein binding annotation is uninformative. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Dual proteome interactome study showing FTL and NCOA4 interactions. Reason: Redundant with existing annotations. Generic protein binding is uninformative. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Multimodal cell maps study showing FTL and NCOA4 interactions. Reason: Redundant with existing annotations. Generic protein binding is uninformative. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	ACCEPT	Summary: FTH1 self-interaction detected in proteome-scale interactome study. This is consistent with the 24-mer homo/heteropolymer assembly of ferritin. Reason: Identical protein binding accurately reflects FTH1 homo-oligomerization within the 24-subunit ferritin shell. While H-ferritin typically forms heteropolymers with L-ferritin, homo-oligomerization of H chains also occurs. Supporting Evidence: PMID:6589621 Ferritin, the main iron-storage protein, is composed of two partially homologous subunits, heavy (H) and light (L) PMID:25416956 A proteome-scale map of the human interactome network.
GO:0042802 identical protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	ACCEPT	Summary: FTH1 self-interaction from genetic variant study. Reason: Consistent with homo-oligomerization in ferritin assembly. Supports the accepted identical protein binding annotation. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0042802 identical protein binding	IPI PMID:33087927 Atomic-resolution protein structure determination by cryo-EM...	ACCEPT	Summary: High-resolution cryo-EM structure demonstrating FTH1 self-assembly in the 24-mer cage. Reason: Structural evidence for FTH1 homo-oligomerization. This is well-established from the extensive crystal and cryo-EM structural data for human ferritin. Supporting Evidence: PMID:33087927 Oct 21. Atomic-resolution protein structure determination by cryo-EM.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation based on immunofluorescence data from the Human Protein Atlas. Cytosolic localization is consistent with ferritin's primary site of function. Reason: Cytosolic localization is a core characteristic of ferritin. The annotation is based on direct imaging evidence and is consistent with ferritin biology.
GO:0110076 negative regulation of ferroptosis	IMP PMID:26403645 Activation of the p62-Keap1-NRF2 pathway protects against fe...	ACCEPT	Summary: This IMP annotation is based on knockdown experiments in hepatocellular carcinoma cells. PMID:26403645 shows that "Knockdown of p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib." FTH1 is transcriptionally activated by NRF2 as part of the antioxidant response. Reason: Negative regulation of ferroptosis is a core function of FTH1. By sequestering labile iron, FTH1 limits iron-mediated lipid peroxidation, the hallmark of ferroptosis. This is experimentally validated and physiologically significant. Supporting Evidence: PMID:26403645 Knockdown of p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib
GO:0004322 ferroxidase activity	IMP PMID:9003196 Dinuclear center of ferritin: studies of iron binding and ox...	ACCEPT	Summary: Direct experimental evidence for ferroxidase activity using stopped-flow assays and site-directed mutagenesis. The study demonstrates that "The ferroxidase activity of human ferritin has previously been associated with a diiron site situated centrally within the four-helix bundle of H-type chains (HuHF)." Reason: Ferroxidase activity is the defining enzymatic function of FTH1. This IMP annotation is based on rigorous biochemical characterization including kinetic analysis and mutagenesis of the ferroxidase center residues (Glu-28, Lys-87, Glu-108). Supporting Evidence: PMID:9003196 The ferroxidase activity of human ferritin has previously been associated with a diiron site situated centrally within the four-helix bundle of H-type chains (HuHF)
GO:0008198 ferrous iron binding	IMP PMID:9003196 Dinuclear center of ferritin: studies of iron binding and ox...	ACCEPT	Summary: Direct experimental evidence for Fe2+ binding at the ferroxidase center using stopped-flow assays and phenanthroline competition. The study dissected binding and oxidation steps, showing sequential binding at sites A and B. Reason: Fe2+ binding is the first step in ferroxidase catalysis and is core to FTH1 function. The IMP evidence from detailed biochemical analysis strongly supports this annotation. Supporting Evidence: PMID:9003196 the first 48 Fe(II) atoms/molecule added are bound and oxidized at the dinuclear centers
GO:0140315 iron ion sequestering activity	IDA PMID:9924025 Coordinated regulation of iron-controlling genes, H-ferritin...	ACCEPT	Summary: PMID:9924025 demonstrates that FTH1 sequesters intracellular iron, and that c-MYC represses FTH1 expression to increase the labile iron pool. The study states that H-ferritin "sequesters intracellular iron." Reason: Iron ion sequestering activity is the primary molecular function of FTH1. The ferritin nanocage physically sequesters iron atoms within its mineral core, removing them from the reactive labile iron pool. This is the functional essence of ferritin. Supporting Evidence: PMID:9924025 the heavy subunit of the protein ferritin (H-ferritin), which sequesters intracellular iron
GO:0044754 autolysosome	IDA PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro...	ACCEPT	Summary: PMID:25327288 demonstrates that NCOA4 delivers ferritin to autolysosomes for degradation. The study shows that "NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex... to autolysosomes following starvation or iron depletion." Reason: Autolysosomal localization is integral to ferritinophagy and ferritin turnover. This represents a physiologically important trafficking step in iron release. Supporting Evidence: PMID:25327288 NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion
GO:1904724 tertiary granule lumen	TAS Reactome:R-HSA-6798745	KEEP AS NON CORE	Summary: Reactome pathway annotation for neutrophil degranulation. Ferritin is found in neutrophil tertiary granules and can be released during degranulation. Reason: Tertiary granule localization in neutrophils represents a cell-type specific localization related to immune function rather than the core iron storage role. This is a valid annotation but peripheral to the main function.
GO:1904813 ficolin-1-rich granule lumen	TAS Reactome:R-HSA-6800434	KEEP AS NON CORE	Summary: Reactome pathway annotation for neutrophil granule content. Similar to tertiary granule annotation. Reason: Cell-type specific localization in neutrophil granules. Valid but peripheral to the core iron storage function.
GO:0005515 protein binding	IPI PMID:15607035 Systematic identification of hepatocellular proteins interac...	MARK AS OVER ANNOTATED	Summary: Interaction with hepatitis C virus NS5A protein identified in systematic hepatocellular protein interaction study. Reason: Viral protein interaction from host-pathogen study. The significance for normal ferritin function is unclear. Generic protein binding is uninformative. Supporting Evidence: PMID:15607035 Systematic identification of hepatocellular proteins interacting with NS5A of the hepatitis C virus.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: High-throughput direct assay (HDA) evidence for exosomal localization from proteomics of urinary exosomes in prostatic secretions. Reason: Exosomal secretion of ferritin has been documented and may contribute to serum ferritin levels and intercellular iron transfer. This is peripheral to the core intracellular iron storage function. Supporting Evidence: PMID:23533145 2013 Apr 23. In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	KEEP AS NON CORE	Summary: Nuclear localization detected in sperm nucleus proteomics. The deep research review notes that nuclear FTH1 (nFTH1) in BRCA1/2-mutant breast cancer predicts shorter survival, suggesting nuclear localization has biological significance. Reason: Nuclear localization of FTH1 has been observed in specific contexts and may have prognostic significance in cancer. However, this is not the primary site of ferritin function. Supporting Evidence: PMID:21630459 Jun 1. Proteomic characterization of the human sperm nucleus.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: Urinary exosome proteomics showing ferritin presence. Reason: Redundant with other exosome annotation. Exosomal secretion is peripheral to core function. Supporting Evidence: PMID:19056867 2008 Dec 3. Large-scale proteomics and phosphoproteomics of urinary exosomes.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6798745	KEEP AS NON CORE	Summary: Reactome pathway annotation related to neutrophil degranulation and secretion. Reason: Extracellular ferritin (serum ferritin) is well-documented and clinically important as a biomarker. Secretion occurs via non-classical pathways. This is peripheral to the core intracellular function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6800434	KEEP AS NON CORE	Summary: Duplicate annotation for extracellular region from Reactome. Reason: Same as above - extracellular presence is documented but peripheral to core function.
GO:0005829 cytosol	TAS Reactome:R-HSA-1562626	ACCEPT	Summary: Reactome pathway annotation for ferritin complex oxidizing Fe2+ to Fe3+. Cytosolic localization is consistent with ferritin's primary function site. Reason: Cytosolic localization is the primary site of ferritin's iron storage function.
GO:0005829 cytosol	TAS Reactome:R-HSA-434362	ACCEPT	Summary: Reactome pathway annotation for recruitment of cytoplasmic proteins to vesicles. Reason: Cytosolic localization is core to ferritin function.
GO:0048147 negative regulation of fibroblast proliferation	IDA PMID:9924025 Coordinated regulation of iron-controlling genes, H-ferritin...	KEEP AS NON CORE	Summary: PMID:9924025 shows that FTH1 expression is repressed by c-MYC, and that "Down-regulation of the expression of H-ferritin gene was required for cell transformation by c-MYC." This indicates FTH1 negatively regulates proliferation. Reason: The anti-proliferative effect of FTH1 is indirect, mediated through iron sequestration reducing the labile iron pool needed for proliferation. This is a downstream consequence rather than a direct molecular function. Supporting Evidence: PMID:9924025 Down-regulation of the expression of H-ferritin gene was required for cell transformation by c-MYC
GO:0006955 immune response	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation based on similarity to UniProtKB:Q8TD27 (FAM81A). The functional relevance of this annotation to FTH1 is unclear. The deep research mentions FTH1's role in Treg lineage stability and immune function through iron provision to TET dioxygenases. Reason: FTH1 does have roles in immune function, particularly in supporting Treg cell stability and iron metabolism in immune cells. However, "immune response" is very broad and the ISS evidence is weak. This is peripheral to core function.
GO:0008285 negative regulation of cell population proliferation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation similar to the fibroblast proliferation annotation. FTH1's iron sequestration function can limit proliferation by reducing labile iron. Reason: Anti-proliferative effects are indirect consequences of iron sequestration rather than a direct molecular function of FTH1. The ISS evidence is weak.
GO:0005506 iron ion binding	TAS PMID:3020541 Cloning, characterization, expression, and chromosomal local...	MODIFY	Summary: TAS annotation from the 1986 paper cloning and characterizing the FTH1 gene. Iron binding is fundamental to ferritin function. Reason: "Iron ion binding" is accurate but less specific than "ferrous iron binding" and "ferric iron binding" which are already annotated. The specific annotations are more informative about the mechanistic role. Proposed replacements: ferrous iron binding ferric iron binding Supporting Evidence: PMID:3020541 Cloning, characterization, expression, and chromosomal localization of a human ferritin heavy-chain gene.
GO:0006879 intracellular iron ion homeostasis	TAS PMID:6589621 Isolation and characterization of a cDNA clone for human fer...	ACCEPT	Summary: The 1984 paper establishing human ferritin H chain cDNA. States that "Ferritin, the main iron-storage protein" highlighting its central role in iron homeostasis. Reason: Intracellular iron ion homeostasis is a core biological process for FTH1. The ferritin system is the primary mechanism for buffering intracellular iron levels. Supporting Evidence: PMID:6589621 Ferritin, the main iron-storage protein, is composed of two partially homologous subunits, heavy (H) and light (L)
GO:0070288 ferritin complex	TAS PMID:6589621 Isolation and characterization of a cDNA clone for human fer...	ACCEPT	Summary: FTH1 is a component of the 24-subunit ferritin complex along with FTL. The heteropolymer assembly is well-characterized structurally. Reason: Membership in the ferritin complex is essential to FTH1's function. The H and L chains assemble into the iron storage nanocage. Supporting Evidence: PMID:6589621 Ferritin, the main iron-storage protein, is composed of two partially homologous subunits, heavy (H) and light (L)

Core Functions

The ferroxidase activity of FTH1 catalyzes oxidation of Fe2+ to Fe3+ at the dinuclear center within the four-helix bundle (EC 1.16.3.1). This is the defining enzymatic function of the ferritin heavy chain that enables safe iron storage within the ferritin mineral core.

Molecular Function:

ferroxidase activity

Directly Involved In:

intracellular iron ion homeostasis

Cellular Locations:

cytosol

In Complex:

ferritin complex

Supporting Evidence:

PMID:9003196
The ferroxidase activity of human ferritin has previously been associated with a diiron site situated centrally within the four-helix bundle of H-type chains

FTH1 sequesters intracellular iron by storing it within the ferritin nanocage as an inert ferrihydrite mineral, buffering the labile iron pool and preventing iron-mediated oxidative damage.

Molecular Function:

iron ion sequestering activity

Directly Involved In:

intracellular iron ion homeostasis negative regulation of ferroptosis

Cellular Locations:

cytosol

In Complex:

ferritin complex

Supporting Evidence:

PMID:9924025
the heavy subunit of the protein ferritin (H-ferritin), which sequesters intracellular iron

FTH1 binds ferrous iron (Fe2+) at the dinuclear ferroxidase center as the first step in the ferroxidase catalytic cycle, with sequential binding at sites A then B.

Molecular Function:

ferrous iron binding

Cellular Locations:

cytosol

In Complex:

ferritin complex

Supporting Evidence:

PMID:9003196
the first 48 Fe(II) atoms/molecule added are bound and oxidized at the dinuclear centers

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:6589621

Isolation and characterization of a cDNA clone for human ferritin heavy chain.

Established that ferritin is the main iron-storage protein composed of H and L subunits

"Ferritin, the main iron-storage protein, is composed of two partially homologous subunits, heavy (H) and light (L)"
Isolated cDNA clone for human ferritin H chain

"We have isolated a cDNA clone for human ferritin H chains by screening a human lymphocyte cDNA library with synthetic oligodeoxyribonucleotides"

PMID:3020541

Cloning, characterization, expression, and chromosomal localization of a human ferritin heavy-chain gene.

Characterized the genomic structure of FTH1 with 4 exons spanning ~3 kb
Localized the gene to chromosome 11

PMID:9003196

Dinuclear center of ferritin: studies of iron binding and oxidation show differences in the two iron sites.

Demonstrated ferroxidase activity at the dinuclear center within H-type chains
Developed stopped-flow assay to dissect Fe2+ binding and oxidation
Showed sequential Fe2+ binding at sites A then B
Mutagenesis of Glu-28, Lys-87, Glu-108 affected iron binding and oxidation

PMID:9924025

Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC.

c-MYC represses FTH1 expression to increase labile iron pool
FTH1 sequesters intracellular iron
Down-regulation of FTH1 required for c-MYC-mediated cell transformation

PMID:24695223

Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy.

Identified NCOA4 as the selective autophagy receptor for ferritin
NCOA4 promotes targeting of ferritin to autolysosomes

PMID:25327288

Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo.

NCOA4 directly binds FTH1 to target ferritin to autolysosomes
Ferritinophagy occurs following starvation or iron depletion
NCOA4 knockout mice accumulate iron in splenic macrophages

PMID:26403645

Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells.

FTH1 is transcriptionally activated by NRF2
FTH1 knockdown promotes ferroptosis in response to erastin and sorafenib
FTH1 is part of the p62-Keap1-NRF2 ferroptosis defense pathway

PMID:26436293

Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis.

Arg-23 is essential for NCOA4 binding
R23A mutation abrogates NCOA4 interaction and lysosomal localization

Reactome:R-HSA-1562626

Ferritin Complex oxidises 4Fe2+ to Fe(3+)O(OH)

Reactome:R-HSA-434362

Recruitment Of Cytoplasmic Proteins To Vesicles

Reactome:R-HSA-6798745

Exocytosis of tertiary granule lumen proteins

Reactome:R-HSA-6800434

Exocytosis of ficolin-rich granule lumen proteins

PMID:15607035

Systematic identification of hepatocellular proteins interacting with NS5A of the hepatitis C virus.

PMID:16169070

A human protein-protein interaction network: a resource for annotating the proteome.

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:17355907

The TSC1 gene product hamartin interacts with NADE.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:20133674

Binding and uptake of H-ferritin are mediated by human transferrin receptor-1.

H-ferritin binds TfR1 for cellular uptake

PMID:20195357

A comprehensive resource of interacting protein regions for refining human transcription factor networks.

PMID:21516116

Next-generation sequencing to generate interactome datasets.

PMID:21573799

FTH1 binds to Daxx and inhibits Daxx-mediated cell apoptosis.

FTH1-DAXX interaction inhibits DAXX-mediated apoptosis

PMID:21630459

Proteomic characterization of the human sperm nucleus.

PMID:21653829

Protein interactome reveals converging molecular pathways among autism disorders.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:22458338

Host-pathogen interactome mapping for HTLV-1 and -2 retroviruses.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

PMID:25277244

The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25910212

Widespread macromolecular interaction perturbations in human genetic disorders.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33087927

Atomic-resolution protein structure determination by cryo-EM.

High-resolution cryo-EM structure of human ferritin

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

file:human/FTH1/FTH1-deep-research-falcon.md

Deep research report on FTH1

📚 Additional Documentation

Deep Research Falcon

(FTH1-deep-research-falcon.md)

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organism_full: Homo sapiens (Human).
protein_family: Belongs to the ferritin family. .
protein_domains: Ferritin. (IPR001519); Ferritin-like. (IPR012347); Ferritin-like_diiron.
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P02794
Protein Description: RecName: Full=Ferritin heavy chain; Short=Ferritin H subunit; EC=1.16.3.1 {ECO:0000269|PubMed:9003196}; AltName: Full=Cell proliferation-inducing gene 15 protein; Contains: RecName: Full=Ferritin heavy chain, N-terminally processed;
Gene Information: Name=FTH1; Synonyms=FTH, FTHL6; ORFNames=OK/SW-cl.84, PIG15;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the ferritin family. .
Key Domains: Ferritin. (IPR001519); Ferritin-like. (IPR012347); Ferritin-like_diiron. (IPR009040); Ferritin-like_SF. (IPR009078); Ferritin_CS. (IPR014034)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "FTH1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'FTH1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene FTH1 (gene ID: FTH1, UniProt: P02794) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P02794
Protein Description: RecName: Full=Ferritin heavy chain; Short=Ferritin H subunit; EC=1.16.3.1 {ECO:0000269|PubMed:9003196}; AltName: Full=Cell proliferation-inducing gene 15 protein; Contains: RecName: Full=Ferritin heavy chain, N-terminally processed;
Gene Information: Name=FTH1; Synonyms=FTH, FTHL6; ORFNames=OK/SW-cl.84, PIG15;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the ferritin family. .
Key Domains: Ferritin. (IPR001519); Ferritin-like. (IPR012347); Ferritin-like_diiron. (IPR009040); Ferritin-like_SF. (IPR009078); Ferritin_CS. (IPR014034)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "FTH1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene FTH1 (gene ID: FTH1, UniProt: P02794) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
We verified identity and scope before research. The target is human ferritin heavy chain (FTH1; UniProt P02794), a 21 kDa subunit of the ferritin family that assembles as a 24‑mer nanocage with ferritin light chain (FTL). FTH1 contains the catalytic ferroxidase center that oxidizes Fe2+ to Fe3+, enabling safe mineral storage; domain annotations match ferritin/ferritin‑like diiron motifs as provided (IPR001519, IPR012347, IPR009040, IPR009078, IPR014034). Organism is Homo sapiens (human). No ambiguity with non‑human genes was used in this report (incocciati2025redesigninghumanferritin pages 31-36, tisci2024engineeredhumanferritins pages 25-32).

Comprehensive research report on human FTH1 (UniProt P02794)

1) Key concepts and definitions with current understanding
- Ferritin architecture and chemistry: Ferritin is a 24‑subunit, ~12 nm outer/8 nm inner diameter protein nanocage that can store up to ~4,000–4,500 iron atoms as a ferrihydrite‑like mineral. Mammalian ferritin is a heteropolymer of heavy (FTH1) and light (FTL) chains; the H‑chain hosts the binuclear ferroxidase center that catalyzes Fe2+ oxidation to Fe3+, while the L‑chain facilitates nucleation/mineral growth. Fe2+ entry occurs mainly via threefold hydrophilic pores and transit is guided by negative electrostatics; the product is immobilized Fe3+ mineral inside the lumen, buffering the labile iron pool and limiting Fenton chemistry (representative parameters and mechanistic details summarized) (https://doi.org/10.3390/biom14060624, Biomolecules, May 2024; and engineering/biophysical summaries) (tisci2024engineeredhumanferritins pages 25-32). Additional mechanistic and structural details for human ferritin are consistent with recent nanotechnology summaries (e.g., channels at threefold and fourfold symmetry axes; H/L functional complementarity) (incocciati2025redesigninghumanferritin pages 31-36).
- Cellular iron homeostasis and regulation: Cytosolic iron exists as a labile Fe2+ pool, imported predominantly via transferrin (TF)–TFRC endocytosis, with endosomal Fe3+ reduced by STEAP3 and exported by DMT1. Excess Fe2+ is stored in ferritin; export occurs via ferroportin (FPN/SLC40A1) coupled to ferroxidases (hephaestin or ceruloplasmin). FTH1 and FTL translation is regulated by IRP1/IRP2 binding to 5′‑UTR IREs (repressing synthesis in iron deficiency), and FTH1 is also transcriptionally induced by NRF2 as part of antioxidant defense (https://doi.org/10.3390/ijms252312987, IJMS, Dec 2024) (ferretti2024theunderestimatedrole pages 6-7, ferretti2024theunderestimatedrole pages 7-9).
- Ferritin turnover and iron release (ferritinophagy): Selective autophagy of ferritin is mediated by cargo receptor NCOA4, delivering ferritin to lysosomes and releasing Fe2+ back to the labile pool; this process couples to ferroptosis susceptibility in multiple contexts (review background) (ferretti2024theunderestimatedrole pages 6-7).
- Systemic/serum ferritin and receptors: Ferritin can be secreted by non‑classical pathways or in extracellular vesicles and circulates as serum ferritin (typically L‑rich), widely used as a biomarker in inflammatory and iron disorders. Exogenous human H‑ferritin binds TfR1 (CD71) and SCARA5, enabling cellular uptake and has been leveraged for drug delivery (technology‑oriented reviews) (incocciati2025redesigninghumanferritin pages 31-36, tisci2024engineeredhumanferritins pages 25-32).

2) Recent developments and latest research (priority 2023–2024)
- Ferritin heteropolymer assembly by cryo‑EM: A 2024 structural study used engineered constructs and high‑resolution cryo‑EM to analyze human heteropolymer ferritin assembly, showing a preference for H–L heterodimer building blocks and stochastic assembly pathways. The work provides mechanistic insight into how H/L subunit ratios and interfaces may tune function in human tissues (https://doi.org/10.1002/pro.5104, Protein Science, Jul 2024) ().
- Ferritinophagy mechanisms and regulation (2024 updates): A 2024 review synthesizes new insights into NCOA4 structure–function and regulation, emphasizing its C‑terminal ferritin‑binding domain and multiple isoforms that fine‑tune ferritin turnover at the immunity–metabolism interface, expanding beyond iron‑dependent roles (https://doi.org/10.1038/s41420-024-02075-3, Cell Death Discovery, Jul 2024). A companion 2024 Cell Proliferation review highlights the double‑edged roles of ferritinophagy within the ferroptosis axis across diseases, consolidating recent evidence and mechanisms (https://doi.org/10.1111/cpr.13621, Feb 2024) (, ).
- FTH1 in ferroptosis and disease (2023–2024 primary data):
• Cancer immunotherapy and prognosis: A 2024 pan‑cancer analysis linked high FTH1 expression to immunotherapy resistance and distinct tumor immune microenvironments, with associations to macrophage infiltration and immune checkpoints, suggesting inhibitory FTH1‑related signaling as a strategy to overcome resistance (https://doi.org/10.1007/s00262-023-03625-x, Cancer Immunol Immunother, Jan 2024) ().
• Pancreatic ductal adenocarcinoma (PDAC): 2024 in vitro/in vivo data show FTH1 interacts with PYCR1 to dysregulate proline metabolism and promote KRAS‑mutant PDAC growth; iron chelator deferasirox suppressed tumor growth by targeting FTH1‑mediated pathways (https://doi.org/10.1038/s12276-024-01300-4, Exp & Mol Med, Sep 2024) ().
• Ovarian cancer chemoresistance: 2024 mechanistic work demonstrated iron promotes malignancy and platinum resistance by enhancing DNA repair via an FTH1/FTL–POLQ/RAD51 axis; iron chelators synergized with platinum in vitro and in vivo (https://doi.org/10.1038/s41419-024-06688-5, Cell Death & Disease, May 2024) ().
• Pediatric AML: 2023 analysis identified high FTH1 expression as a poor prognostic factor; functional assays indicated that FTH1 upregulation promoted proliferation and inhibited apoptosis via the ferroptosis pathway (https://doi.org/10.3389/fonc.2022.1068094, Frontiers in Oncology, Feb 2023) ().
- Immune cell biology (2024): EMBO Journal reported that FTH supports regulatory T cell (Treg) lineage stability by providing iron for TET dioxygenases that maintain FOXP3 locus demethylation, thereby sustaining FOXP3 expression and immune homeostasis; the FTH ferroxidase function was mechanistically implicated (https://doi.org/10.1038/s44318-024-00064-x, EMBO J, Mar 2024) ().
- CNS and systemic context: 2024 narrative review summarized ferritin’s central role in CNS iron homeostasis, including secretion in EVs and intercellular transfer (e.g., microglia to oligodendrocytes), and emphasized translational regulation of FTH1 by IRP/IRE and NRF2 (https://doi.org/10.3390/ijms252312987, IJMS, Dec 2024) (ferretti2024theunderestimatedrole pages 2-4, ferretti2024theunderestimatedrole pages 6-7, ferretti2024theunderestimatedrole pages 7-9).

3) Subcellular localization and trafficking
- Primary localization: Ferritin is predominantly cytosolic. Human ferritin can also localize to lysosomes (during ferritinophagy), nucleus, and mitochondria; mitochondrial ferritin (FTMT) is a separate gene, but cytosolic ferritin has been detected in organellar contexts in some studies and reviews (summarized in translational nanotechnology overviews of human H‑ferritin) (incocciati2025redesigninghumanferritin pages 31-36).
- Ferritinophagy routing: NCOA4 binds ferritin and traffics the complex to autophagosomes for lysosomal degradation, releasing iron to the labile pool; inhibition of autophagy or NCOA4 limits ferritin iron release and ferroptotic sensitivity in multiple disease models (updated reviews, 2024) (, ).
- Nuclear localization and clinical relevance: In BRCA1/2‑mutant breast cancer, nuclear FTH1 (nFTH1), but not cytoplasmic FTH1, independently predicted shorter disease‑free and metastasis‑free survival, highlighting a trafficking/localization phenotype with prognostic value (HR for DFS 2.71 [1.49–4.92]) (https://doi.org/10.3390/cancers16010028, Cancers, Dec 2023) ().
- Secretion and extracellular ferritin: Non‑classical secretion and EV‑associated ferritin are described in CNS and systemic contexts; serum ferritin is clinically used in inflammation and iron disorders and is enriched for L‑chain, but receptor‑mediated uptake of H‑ferritin via TfR1 and SCARA5 is well established (incocciati2025redesigninghumanferritin pages 31-36, ferretti2024theunderestimatedrole pages 6-7).

4) Current applications and real‑world implementations
- Diagnostic biomarkers:
• Serum ferritin is widely used as a biomarker across infection/inflammation and cardiometabolic risk; translational reviews reaffirm this use-case and note L‑rich composition in serum ferritin (technology and biology summaries) (incocciati2025redesigninghumanferritin pages 31-36).
• Tumor tissue biomarkers: FTH1 immunohistochemistry and subcellular localization can carry prognostic information (e.g., nuclear FTH1 in BRCA1/2‑mutant breast cancer predicts worse recurrence‑free and metastasis‑free survival) (https://doi.org/10.3390/cancers16010028, Dec 2023). Pan‑cancer analyses linked high FTH1 to immunotherapy resistance, suggesting stratification value (https://doi.org/10.1007/s00262-023-03625-x, Jan 2024) (, ).
- Therapeutic and imaging platforms (ferritin nanocages): Human H‑ferritin binds TfR1 and can be engineered for targeted delivery; methods include pH‑driven disassembly/reassembly for cargo loading, lumenal charge mutations, and surface functionalization. Reported applications span chemotherapy payloads, imaging (e.g., gadolinium‑loaded HFn), and combination modalities. Reviews outline opportunities and translational hurdles (e.g., receptor heterogeneity, clearance, scale‑up) and report use in preclinical oncology models; serum‑stable designs (PASylation/XTEN) are under evaluation (https://doi.org/10.3390/biom14060624, May 2024; Expert review overview, Nov 2025 online) (tisci2024engineeredhumanferritins pages 25-32, giacobbo2026progressandpotential pages 1-3).
- Therapeutic strategy (iron and ferroptosis modulation): In PDAC, iron chelation with deferasirox reduced growth by modulating FTH1‑mediated pathways (https://doi.org/10.1038/s12276-024-01300-4, Sep 2024); in ovarian cancer, iron depletion synergized with platinum therapy, mechanistically dependent on ferritin heavy/light chain regulation of DNA repair components (https://doi.org/10.1038/s41419-024-06688-5, May 2024) (, ).

5) Expert opinions, statistics, and quantitative data from recent studies
- Quantitative structural/biophysical parameters: Ferritin cage dimensions (~12 nm outer, ~8 nm inner) and storage capacity (~4,000–4,500 Fe atoms) are consistently reported across 2024 structural/nanotech reviews; entry channels and ferroxidase activity are emphasized as key determinants of iron handling (tisci2024engineeredhumanferritins pages 25-32, incocciati2025redesigninghumanferritin pages 31-36).
- Clinical statistics and prognostic effect sizes:
• Breast cancer (BRCA1/2 mutation carriers): Nuclear FTH1 associated with shorter disease‑free survival (HR 2.71, 95% CI 1.49–4.92, p=0.001) and metastasis‑free survival (HR 3.54, 95% CI 1.45–8.66, p=0.006) in multivariable analyses (https://doi.org/10.3390/cancers16010028, Dec 2023) ().
• Pan‑cancer immunotherapy: High FTH1 correlated with reduced benefit from immunotherapy and with macrophage infiltration and immune checkpoint expression across multiple cancers in bioinformatic analyses (https://doi.org/10.1007/s00262-023-03625-x, Jan 2024) ().
• PDAC mechanistic efficacy: Deferasirox reduced viability and tumor growth in KRAS‑mutant PDAC models by targeting the FTH1–PYCR1 axis affecting proline metabolism (https://doi.org/10.1038/s12276-024-01300-4, Sep 2024) ().
• Ovarian cancer mechanistic synergy: Iron chelators plus platinum produced synergistic antitumor effects in vitro and in vivo, with the FTH1/FTL–POLQ/RAD51 axis underpinning iron‑driven DNA repair and resistance (https://doi.org/10.1038/s41419-024-06688-5, May 2024) ().
- Immune cell mechanism: FTH1 supports Treg FOXP3 locus demethylation via enabling TET dioxygenase activity, functionally sustaining Treg lineage and impacting autoimmune neuroinflammation and tumor progression in mouse models (https://doi.org/10.1038/s44318-024-00064-x, Mar 2024) ().

Pathways and primary function, with substrate specificity and localization
- Enzymatic function: FTH1’s ferroxidase center binds Fe2+ and O2 to oxidize Fe2+ to Fe3+, producing an Fe(III) mineral within the 24‑mer lumen; the substrate specificity is ferrous iron (Fe2+) and molecular oxygen, and the reaction product is ferric iron (Fe3+) coordinated in a ferrihydrite‑like mineral. This reaction reduces reactive ferrous iron and supports safe storage, central to iron metabolism and protection from oxidative damage (tisci2024engineeredhumanferritins pages 25-32, incocciati2025redesigninghumanferritin pages 31-36).
- Pathways: FTH1 acts within cellular iron handling (TF/TFRC uptake; IRP/IRE control), ferritinophagy (NCOA4‑mediated lysosomal turnover), ferroptosis (buffering labile iron to limit lipid peroxidation), immune regulation (support of TET enzymes in Tregs), and cancer metabolic rewiring (e.g., proline metabolism in KRAS‑mutant PDAC; DNA repair in ovarian cancer) (, , , , , ).
- Localization: FTH1 functions primarily in the cytosol within ferritin shells; it traffics to autophagosomes/lysosomes during ferritinophagy; nuclear localization has been observed in tumor settings with prognostic implications; extracellular/serum ferritin reflects secretory and EV pathways. Uptake of exogenous H‑ferritin occurs via TfR1 and SCARA5 (incocciati2025redesigninghumanferritin pages 31-36, ferretti2024theunderestimatedrole pages 6-7).

Expert synthesis and outlook
- Consensus across 2023–2024 publications: FTH1 remains central to iron buffering and ferroxidation, with emerging roles in immune regulation and tumor biology through ferroptosis coupling and metabolic co‑dependencies. Manipulating ferritin turnover (NCOA4) or FTH1 expression can modulate ferroptosis and therapeutic responses. Translationally, H‑ferritin nanocages present a promising but still maturing platform for targeted delivery via TfR1; variability in receptor expression and pharmacokinetics are recognized hurdles (tisci2024engineeredhumanferritins pages 25-32, giacobbo2026progressandpotential pages 1-3).

References with URLs and dates (selection used above)
- Eren E, Watts NR, Montecinos F, Wingfield PT. Encapsulated Ferritin-like Proteins: A Structural Perspective. Biomolecules. May 2024. https://doi.org/10.3390/biom14060624 (tisci2024engineeredhumanferritins pages 25-32)
- Incocciati A. Redesigning human ferritin nanocages for therapeutic applications: from cancer treatment to hypercholesterolemia management. 2025 (review summarizing H‑ferritin biology and engineering). (incocciati2025redesigninghumanferritin pages 31-36)
- Ferretti S, Zanella I. The Underestimated Role of Iron in Frontotemporal Dementia. IJMS. Dec 2024. https://doi.org/10.3390/ijms252312987 (ferretti2024theunderestimatedrole pages 2-4, ferretti2024theunderestimatedrole pages 6-7, ferretti2024theunderestimatedrole pages 7-9)
- Li J‑Y et al. Ferritinophagy: double‑edged sword in ferritinophagy–ferroptosis axis. Cell Prolif. Feb 2024. https://doi.org/10.1111/cpr.13621 ()
- Le Y et al. Emerging role of NCOA4 in health and disease. Cell Death Discovery. Jul 2024. https://doi.org/10.1038/s41420-024-02075-3 ()
- Luo Y et al. Pan‑cancer analysis of FTH1 in immunotherapy. Cancer Immunol Immunother. Jan 2024. https://doi.org/10.1007/s00262-023-03625-x ()
- Park JM et al. Crosstalk between FTH1 and PYCR1 in KRAS‑mutant PDAC. Exp & Mol Med. Sep 2024. https://doi.org/10.1038/s12276-024-01300-4 ()
- Zhang Q et al. Iron promotes ovarian cancer resistance via FTH1/FTL/POLQ/RAD51. Cell Death & Disease. May 2024. https://doi.org/10.1038/s41419-024-06688-5 ()
- Zhang J et al. High FTH1 in pediatric AML prognosis. Front Oncol. Feb 2023. https://doi.org/10.3389/fonc.2022.1068094 ()
- Wu Q et al. FTH supports Treg lineage. EMBO J. Mar 2024. https://doi.org/10.1038/s44318-024-00064-x ()
- Bou‑Abdallah F et al. Heteropolymer ferritin assembly by cryo‑EM. Protein Sci. Jul 2024. https://doi.org/10.1002/pro.5104 ()
- Giacobbo V et al. Ferritin nanocages for cancer drug delivery. Expert Opin Drug Deliv. Online Nov 2025. https://doi.org/10.1080/17425247.2025.2584632 (giacobbo2026progressandpotential pages 1-3)
- Qu S et al. Nuclear FTH1 predicts recurrence in BRCA1/2‑mutant BC. Cancers. Dec 2023. https://doi.org/10.3390/cancers16010028 ()

Limitations
- Some translational/engineering sources are technology reviews (2024–2025) and should be interpreted alongside primary mechanistic papers. Where available, 2023–2024 primary literature was prioritized; older consensus biochemistry of ferritin was used for core definitions. (tisci2024engineeredhumanferritins pages 25-32, incocciati2025redesigninghumanferritin pages 31-36)

References

(incocciati2025redesigninghumanferritin pages 31-36): A Incocciati. Redesigning human ferritin nanocages for therapeutic applications: from cancer treatment to hypercholesterolemia management. Unknown journal, 2025.
(tisci2024engineeredhumanferritins pages 25-32): G Tisci. Engineered human ferritins for the selective delivery of bioactive molecules to pathological sites. Unknown journal, 2024.
(ferretti2024theunderestimatedrole pages 6-7): Sara Ferretti and Isabella Zanella. The underestimated role of iron in frontotemporal dementia: a narrative review. International Journal of Molecular Sciences, 25:12987, Dec 2024. URL: https://doi.org/10.3390/ijms252312987, doi:10.3390/ijms252312987. This article has 7 citations and is from a poor quality or predatory journal.
(ferretti2024theunderestimatedrole pages 7-9): Sara Ferretti and Isabella Zanella. The underestimated role of iron in frontotemporal dementia: a narrative review. International Journal of Molecular Sciences, 25:12987, Dec 2024. URL: https://doi.org/10.3390/ijms252312987, doi:10.3390/ijms252312987. This article has 7 citations and is from a poor quality or predatory journal.
(ferretti2024theunderestimatedrole pages 2-4): Sara Ferretti and Isabella Zanella. The underestimated role of iron in frontotemporal dementia: a narrative review. International Journal of Molecular Sciences, 25:12987, Dec 2024. URL: https://doi.org/10.3390/ijms252312987, doi:10.3390/ijms252312987. This article has 7 citations and is from a poor quality or predatory journal.
(giacobbo2026progressandpotential pages 1-3): Valeria Giacobbo, Francesca Gorgoglione, Marta Sevieri, Beatrice Bignami, Ilaria Tagliolini, Fabio Corsi, and Serena Mazzucchelli. Progress and potential of ferritin nanocages for cancer drug delivery. Expert Opinion on Drug Delivery, pages 1-14, Nov 2026. URL: https://doi.org/10.1080/17425247.2025.2584632, doi:10.1080/17425247.2025.2584632. This article has 0 citations and is from a peer-reviewed journal.

Citations

tisci2024engineeredhumanferritins pages 25-32
incocciati2025redesigninghumanferritin pages 31-36
ferretti2024theunderestimatedrole pages 6-7
giacobbo2026progressandpotential pages 1-3
ferretti2024theunderestimatedrole pages 7-9
ferretti2024theunderestimatedrole pages 2-4
1.49–4.92
https://doi.org/10.3390/biom14060624,
https://doi.org/10.3390/ijms252312987,
https://doi.org/10.1002/pro.5104,
https://doi.org/10.1038/s41420-024-02075-3,
https://doi.org/10.1111/cpr.13621,
https://doi.org/10.1007/s00262-023-03625-x,
https://doi.org/10.1038/s12276-024-01300-4,
https://doi.org/10.1038/s41419-024-06688-5,
https://doi.org/10.3389/fonc.2022.1068094,
https://doi.org/10.1038/s44318-024-00064-x,
https://doi.org/10.3390/cancers16010028,
https://doi.org/10.3390/biom14060624
https://doi.org/10.3390/ijms252312987
https://doi.org/10.1111/cpr.13621
https://doi.org/10.1038/s41420-024-02075-3
https://doi.org/10.1007/s00262-023-03625-x
https://doi.org/10.1038/s12276-024-01300-4
https://doi.org/10.1038/s41419-024-06688-5
https://doi.org/10.3389/fonc.2022.1068094
https://doi.org/10.1038/s44318-024-00064-x
https://doi.org/10.1002/pro.5104
https://doi.org/10.1080/17425247.2025.2584632
https://doi.org/10.3390/cancers16010028
https://doi.org/10.1080/17425247.2025.2584632,

📄 View Raw YAML

id: P02794
gene_symbol: FTH1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: FTH1 encodes the ferritin heavy chain, a 21 kDa subunit of the 
  ferritin complex that assembles as a 24-mer nanocage (~12 nm outer diameter, 
  ~8 nm inner cavity) with ferritin light chain (FTL). The heavy chain contains 
  the binuclear ferroxidase center that catalyzes oxidation of Fe2+ to Fe3+ (EC 
  1.16.3.1), enabling safe storage of up to 4,500 iron atoms as ferrihydrite 
  mineral within the protein shell. FTH1 is central to intracellular iron 
  homeostasis, buffering the labile iron pool and limiting Fenton 
  chemistry-mediated oxidative damage. The protein is regulated 
  post-transcriptionally by IRP1/IRP2 via 5'-UTR iron-responsive elements 
  (IREs), and transcriptionally by NRF2 as part of antioxidant defense. Ferritin
  turnover occurs via ferritinophagy, mediated by the cargo receptor NCOA4 which
  binds FTH1 at Arg-23 to target ferritin to autolysosomes for degradation and 
  iron release. FTH1 plays a critical role in negative regulation of ferroptosis
  by sequestering iron and limiting lipid peroxidation. Mutations in FTH1 cause 
  hemochromatosis type 5 (IRE mutation) and neurodegeneration with brain iron 
  accumulation type 9.
existing_annotations:
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Ferritin is a predominantly cytoplasmic protein in mammalian 
        cells. The IBA annotation based on phylogenetic inference is 
        well-supported by the UniProt subcellular location annotation which 
        states "Cytoplasm" with experimental evidence (PMID:26436293). Crystal 
        structures and functional studies consistently show cytoplasmic 
        localization of the ferritin complex.
      action: ACCEPT
      reason: The cytoplasmic localization of FTH1 is a core functional 
        characteristic. The 24-mer ferritin nanocage forms in the cytoplasm 
        where it performs its iron storage function. This is supported by 
        extensive structural and cell biological evidence.
      supported_by:
        - reference_id: PMID:26436293
          supporting_text: NCOA4 is a selective cargo receptor for the 
            autophagic turnover of ferritin, a process critical for regulation 
            of intracellular iron bioavailability
        - reference_id: file:human/FTH1/FTH1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0008198
      label: ferrous iron binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Ferrous iron (Fe2+) binding is the initial step in ferritin's 
        iron storage mechanism. The IBA annotation is strongly supported by 
        direct experimental evidence from PMID:9003196 which used stopped-flow 
        assays and site-directed mutagenesis to demonstrate Fe2+ binding at the 
        ferroxidase center, showing that "the first 48 Fe(II) atoms/molecule 
        added are bound and oxidized at the dinuclear centers."
      action: ACCEPT
      reason: Fe2+ binding is essential to FTH1's core ferroxidase function. The
        ferritin H chain binds Fe2+ at its dinuclear ferroxidase center (sites A
        and B) prior to oxidation. This is experimentally validated and central 
        to the protein's physiological role.
      supported_by:
        - reference_id: PMID:9003196
          supporting_text: the first 48 Fe(II) atoms/molecule added are bound 
            and oxidized at the dinuclear centers
  - term:
      id: GO:0006826
      label: iron ion transport
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Iron ion transport describes the movement of iron ions. While 
        FTH1 is involved in iron handling, its primary role is iron storage 
        rather than active transport. The UniProt function annotation states 
        FTH1 "Stores iron in a soluble, non-toxic, readily available form" and 
        "Also plays a role in delivery of iron to cells" but this delivery 
        function is attributed to the assembled ferritin complex being taken up 
        by cells, not direct transport activity.
      action: MODIFY
      reason: FTH1's primary function is iron sequestration and storage, not 
        active transport. The term "iron ion transport" implies movement across 
        membranes or between compartments, whereas ferritin accumulates iron 
        within its mineral core. Iron release occurs via ferritinophagy 
        (lysosomal degradation), not a transport mechanism intrinsic to FTH1.
      proposed_replacement_terms:
        - id: GO:0006879
          label: intracellular iron ion homeostasis
  - term:
      id: GO:0008199
      label: ferric iron binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Ferric iron (Fe3+) is the oxidized form stored within the 
        ferritin mineral core. The deep research confirms that FTH1 catalyzes 
        "oxidation of Fe2+ to Fe3+, producing an Fe(III) mineral within the 
        24-mer lumen." The ferric iron is coordinated in a ferrihydrite-like 
        mineral structure.
      action: ACCEPT
      reason: Fe3+ binding/storage is the end product of FTH1's ferroxidase 
        activity. The ferrihydrite mineral core contains coordinated Fe3+ ions. 
        This is central to the iron storage function of ferritin.
      supported_by:
        - reference_id: PMID:9003196
          supporting_text: The ferroxidase activity of human ferritin has 
            previously been associated with a diiron site situated centrally 
            within the four-helix bundle of H-type chains
  - term:
      id: GO:0004322
      label: ferroxidase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'The IEA annotation based on EC number mapping (EC 1.16.3.1) is appropriate.
        FTH1''s ferroxidase activity is well-established experimentally, with the
        catalytic reaction: 4 Fe(2+) + O2 + 4 H(+) = 4 Fe(3+) + 2 H2O. This is validated
        by direct experimental evidence in PMID:9003196.'
      action: ACCEPT
      reason: Ferroxidase activity is the defining enzymatic function of the 
        ferritin heavy chain. The dinuclear ferroxidase center in FTH1 oxidizes 
        Fe2+ to Fe3+ coupled to oxygen reduction. This is the mechanistic basis 
        for ferritin's iron storage capacity and distinguishes the H chain from 
        the L chain.
      supported_by:
        - reference_id: PMID:9003196
          supporting_text: The ferroxidase activity of human ferritin has 
            previously been associated with a diiron site situated centrally 
            within the four-helix bundle of H-type chains
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Duplicate annotation for cytoplasmic localization with IEA 
        evidence based on UniProtKB subcellular location vocabulary mapping. 
        Consistent with the IBA annotation above.
      action: ACCEPT
      reason: Cytoplasmic localization is well-supported and a core 
        characteristic. This annotation is redundant with the IBA annotation but
        correctly captures the primary subcellular location.
  - term:
      id: GO:0005764
      label: lysosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Lysosomal localization of ferritin occurs during ferritinophagy. 
        PMID:26436293 demonstrates that ferritin is delivered to lysosomes via 
        NCOA4-mediated autophagy. UniProt subcellular location annotation 
        confirms "Lysosome" with experimental evidence.
      action: ACCEPT
      reason: Lysosomal targeting is integral to ferritin's physiological 
        turnover and iron release mechanism. NCOA4-mediated ferritinophagy 
        delivers FTH1-containing complexes to lysosomes for degradation, which 
        is essential for iron recycling.
      supported_by:
        - reference_id: PMID:26436293
          supporting_text: direct association via a key surface arginine in FTH1
            and a C-terminal element in NCOA4 is required for delivery of 
            ferritin to the lysosome via autophagosomes
  - term:
      id: GO:0005776
      label: autophagosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Autophagosome localization reflects ferritinophagy, where NCOA4 
        delivers ferritin to autophagosomes for eventual lysosomal degradation. 
        This is supported by UniProt annotation "Cytoplasmic vesicle, 
        autophagosome" with experimental evidence from PMID:24695223.
      action: ACCEPT
      reason: Autophagosome localization is part of the ferritinophagy pathway. 
        NCOA4 binds ferritin and traffics the complex to autophagosomes prior to
        lysosomal fusion. This is physiologically important for regulated iron 
        release.
      supported_by:
        - reference_id: PMID:24695223
          supporting_text: delivery of ferritin to lysosomes required NCOA4, and
            an inability of NCOA4-deficient cells to degrade ferritin led to 
            decreased bioavailable intracellular iron
  - term:
      id: GO:0006826
      label: iron ion transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Duplicate annotation for iron ion transport from InterPro domain 
        mapping. Same considerations apply as for the IBA annotation.
      action: MODIFY
      reason: FTH1's primary function is iron sequestration/storage within the 
        ferritin shell, not active membrane transport. While iron enters and 
        exits the ferritin cage, this is not a transport function in the GO 
        sense.
      proposed_replacement_terms:
        - id: GO:0006879
          label: intracellular iron ion homeostasis
  - term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: FTH1 is central to intracellular iron homeostasis through its 
        iron storage function. By sequestering excess iron as inert ferric 
        mineral, FTH1 buffers the labile iron pool and prevents iron-mediated 
        toxicity. This is supported by the deep research review and TAS 
        annotation from PMID:6589621.
      action: ACCEPT
      reason: Intracellular iron ion homeostasis accurately describes FTH1's 
        physiological role. The ferritin system maintains iron balance by 
        storing excess iron and releasing it when needed through ferritinophagy.
      supported_by:
        - reference_id: PMID:6589621
          supporting_text: Ferritin, the main iron-storage protein, is composed 
            of two partially homologous subunits, heavy (H) and light (L)
  - term:
      id: GO:0008199
      label: ferric iron binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Duplicate annotation for ferric iron binding from InterPro domain
        mapping. Same considerations apply as for the IBA annotation.
      action: ACCEPT
      reason: Fe3+ binding/storage is central to ferritin function. The IEA 
        annotation is consistent with the IBA annotation and well-supported by 
        experimental evidence.
  - term:
      id: GO:0016491
      label: oxidoreductase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: The oxidoreductase activity annotation is accurate but too 
        general. FTH1 has the more specific ferroxidase activity (GO:0004322) 
        which is already annotated. The general oxidoreductase term does not add
        informative value.
      action: MARK_AS_OVER_ANNOTATED
      reason: While technically correct (ferroxidase is an oxidoreductase), this
        term is too broad to be informative. The specific ferroxidase activity 
        annotation (GO:0004322) provides the functionally relevant information.
  - term:
      id: GO:0031410
      label: cytoplasmic vesicle
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Cytoplasmic vesicle is a broad term that encompasses 
        autophagosomes. The more specific autophagosome annotation (GO:0005776) 
        is already present. This general annotation is less informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: The specific autophagosome localization is already captured. 
        "Cytoplasmic vesicle" is too general to be maximally informative when 
        more specific terms are annotated.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Metal ion binding is extremely general. FTH1 has specific 
        annotations for ferrous and ferric iron binding which are much more 
        informative. This general term does not add value.
      action: MARK_AS_OVER_ANNOTATED
      reason: FTH1 is specifically an iron-binding protein, not a general metal 
        binder. The specific ferrous iron binding (GO:0008198) and ferric iron 
        binding (GO:0008199) annotations provide the relevant functional 
        information.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16169070
    review:
      summary: High-throughput protein-protein interaction data showing 
        interaction with FTL (P02792). The FTH1-FTL interaction is biologically 
        meaningful for ferritin heteropolymer assembly.
      action: MARK_AS_OVER_ANNOTATED
      reason: While the FTH1-FTL interaction is functionally important for 
        ferritin assembly, "protein binding" is uninformative. The identical 
        protein binding annotation captures homo-oligomerization, but a more 
        specific term for hetero-oligomerization with FTL would be more 
        valuable.
      supported_by:
        - reference_id: PMID:16169070
          supporting_text: 'A human protein-protein interaction network: a resource
            for annotating the proteome.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16189514
    review:
      summary: High-throughput PPI data showing interactions with FTL (P02792) 
        and FXR2 (P51116). The FTL interaction is functionally relevant.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding annotation provides minimal functional 
        insight. The FTL interaction reflects ferritin heteropolymer assembly; 
        other interactions require validation for functional relevance.
      supported_by:
        - reference_id: PMID:16189514
          supporting_text: Towards a proteome-scale map of the human 
            protein-protein interaction network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17355907
    review:
      summary: Interaction with TSC1 (Q92574) hamartin reported. The functional 
        significance of this interaction is unclear from available literature.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding annotation. The biological relevance of 
        the FTH1-TSC1 interaction is not well established in the context of 
        ferritin's iron storage function.
      supported_by:
        - reference_id: PMID:17355907
          supporting_text: 2007 Feb 12. The TSC1 gene product hamartin interacts
            with NADE.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20133674
    review:
      summary: Interaction with TFRC (P02786, transferrin receptor 1). This 
        interaction is functionally meaningful as TfR1 mediates cellular uptake 
        of extracellular H-ferritin.
      action: KEEP_AS_NON_CORE
      reason: The FTH1-TFRC interaction is biologically significant for 
        H-ferritin uptake, but this represents an extracellular signaling/uptake
        function rather than the core intracellular iron storage function. A 
        more specific MF term would be preferable.
      supported_by:
        - reference_id: PMID:20133674
          supporting_text: Binding and uptake of H-ferritin are mediated by 
            human transferrin receptor-1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20195357
    review:
      summary: Interaction with MAX (P61244) transcription factor. The 
        functional significance of this interaction is unclear.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding annotation from high-throughput study. The
        biological relevance of the FTH1-MAX interaction is not established.
      supported_by:
        - reference_id: PMID:20195357
          supporting_text: A comprehensive resource of interacting protein 
            regions for refining human transcription factor networks.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21516116
    review:
      summary: Next-generation sequencing interactome study showing FTL 
        interaction.
      action: MARK_AS_OVER_ANNOTATED
      reason: Redundant with other FTH1-FTL interaction annotations. Generic 
        protein binding is uninformative.
      supported_by:
        - reference_id: PMID:21516116
          supporting_text: Next-generation sequencing to generate interactome 
            datasets.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21573799
    review:
      summary: FTH1 binds DAXX (Q9UER7) and inhibits DAXX-mediated cell 
        apoptosis. This represents a specific functional interaction.
      action: KEEP_AS_NON_CORE
      reason: The FTH1-DAXX interaction appears to have functional consequences 
        for apoptosis regulation. However, this represents a secondary/non-core 
        function rather than the primary iron storage role. The generic "protein
        binding" term is still uninformative - a more specific term would be 
        preferable.
      supported_by:
        - reference_id: PMID:21573799
          supporting_text: May 15. FTH1 binds to Daxx and inhibits Daxx-mediated
            cell apoptosis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21653829
    review:
      summary: High-throughput study on autism-related protein interactome 
        showing FXR2 and TSC1 interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic protein binding from high-throughput study. The biological
        relevance of these interactions to ferritin function is unclear.
      supported_by:
        - reference_id: PMID:21653829
          supporting_text: Protein interactome reveals converging molecular 
            pathways among autism disorders.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21988832
    review:
      summary: Liver protein interactome study showing DAXX interaction.
      action: MARK_AS_OVER_ANNOTATED
      reason: Redundant with other DAXX interaction annotation. Generic protein 
        binding is uninformative.
      supported_by:
        - reference_id: PMID:21988832
          supporting_text: Toward an understanding of the protein interaction 
            network of the human liver.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22458338
    review:
      summary: Host-pathogen interactome study showing interaction with HTLV HBZ
        protein (Q2Q067).
      action: MARK_AS_OVER_ANNOTATED
      reason: Viral protein interaction from host-pathogen study. The biological
        significance for normal ferritin function is unclear. Generic protein 
        binding is uninformative.
      supported_by:
        - reference_id: PMID:22458338
          supporting_text: Host-pathogen interactome mapping for HTLV-1 and -2 
            retroviruses.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25277244
    review:
      summary: Interaction with HSPB1/Hsp27 (P04792) from functional landscape 
        study.
      action: MARK_AS_OVER_ANNOTATED
      reason: The biological significance of the FTH1-HSPB1 interaction is 
        unclear. Generic protein binding annotation is uninformative.
      supported_by:
        - reference_id: PMID:25277244
          supporting_text: Epub 2014 Oct 2. The functional landscape of Hsp27 
            reveals new cellular processes such as DNA repair and alternative 
            splicing and proposes novel anticancer targets.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25327288
    review:
      summary: Interaction with NCOA4 (Q13772), the cargo receptor that mediates
        ferritinophagy. This is a critical functional interaction for ferritin 
        turnover.
      action: ACCEPT
      reason: The FTH1-NCOA4 interaction is functionally essential for 
        ferritinophagy and iron homeostasis. NCOA4 binds FTH1 at Arg-23 to 
        target ferritin to autolysosomes. While "protein binding" is generic, 
        this specific interaction is core to ferritin biology.
      supported_by:
        - reference_id: PMID:25327288
          supporting_text: NCOA4 directly binds ferritin heavy chain-1 (FTH1) to
            target the iron-binding ferritin complex with a relative molecular 
            mass of 450,000 to autolysosomes following starvation or iron 
            depletion
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: Proteome-scale interactome map showing FTL interaction.
      action: MARK_AS_OVER_ANNOTATED
      reason: Redundant with other FTH1-FTL interaction annotations. Generic 
        protein binding is uninformative.
      supported_by:
        - reference_id: PMID:25416956
          supporting_text: A proteome-scale map of the human interactome 
            network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25910212
    review:
      summary: Study on genetic variant effects on protein interactions, showing
        FTL interaction.
      action: MARK_AS_OVER_ANNOTATED
      reason: Redundant FTL interaction annotation. Generic protein binding is 
        uninformative.
      supported_by:
        - reference_id: PMID:25910212
          supporting_text: Widespread macromolecular interaction perturbations 
            in human genetic disorders.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: Human interactome architecture study showing FTL and NCOA4 
        interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Redundant with existing annotations. The NCOA4 interaction is 
        accepted elsewhere. Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: Architecture of the human interactome defines protein
            communities and disease networks.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31515488
    review:
      summary: Study on genetic variant disruption of protein interactions, 
        showing FTL and FXR2 interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Redundant FTL interaction annotation. Generic protein binding is 
        uninformative.
      supported_by:
        - reference_id: PMID:31515488
          supporting_text: Extensive disruption of protein interactions by 
            genetic variants across the allele frequency spectrum in human 
            populations.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: Reference interactome map showing BAG4 (O95429) interaction.
      action: MARK_AS_OVER_ANNOTATED
      reason: The biological significance of FTH1-BAG4 interaction is unclear. 
        Generic protein binding annotation is uninformative.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: Apr 8. A reference map of the human binary protein 
            interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Dual proteome interactome study showing FTL and NCOA4 
        interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Redundant with existing annotations. Generic protein binding is 
        uninformative.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: Multimodal cell maps study showing FTL and NCOA4 interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Redundant with existing annotations. Generic protein binding is 
        uninformative.
      supported_by:
        - reference_id: PMID:40205054
          supporting_text: Apr 9. Multimodal cell maps as a foundation for 
            structural and functional genomics.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: FTH1 self-interaction detected in proteome-scale interactome 
        study. This is consistent with the 24-mer homo/heteropolymer assembly of
        ferritin.
      action: ACCEPT
      reason: Identical protein binding accurately reflects FTH1 
        homo-oligomerization within the 24-subunit ferritin shell. While 
        H-ferritin typically forms heteropolymers with L-ferritin, 
        homo-oligomerization of H chains also occurs.
      supported_by:
        - reference_id: PMID:6589621
          supporting_text: Ferritin, the main iron-storage protein, is composed 
            of two partially homologous subunits, heavy (H) and light (L)
        - reference_id: PMID:25416956
          supporting_text: A proteome-scale map of the human interactome 
            network.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:31515488
    review:
      summary: FTH1 self-interaction from genetic variant study.
      action: ACCEPT
      reason: Consistent with homo-oligomerization in ferritin assembly. 
        Supports the accepted identical protein binding annotation.
      supported_by:
        - reference_id: PMID:31515488
          supporting_text: Extensive disruption of protein interactions by 
            genetic variants across the allele frequency spectrum in human 
            populations.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:33087927
    review:
      summary: High-resolution cryo-EM structure demonstrating FTH1 
        self-assembly in the 24-mer cage.
      action: ACCEPT
      reason: Structural evidence for FTH1 homo-oligomerization. This is 
        well-established from the extensive crystal and cryo-EM structural data 
        for human ferritin.
      supported_by:
        - reference_id: PMID:33087927
          supporting_text: Oct 21. Atomic-resolution protein structure 
            determination by cryo-EM.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: IDA annotation based on immunofluorescence data from the Human 
        Protein Atlas. Cytosolic localization is consistent with ferritin's 
        primary site of function.
      action: ACCEPT
      reason: Cytosolic localization is a core characteristic of ferritin. The 
        annotation is based on direct imaging evidence and is consistent with 
        ferritin biology.
  - term:
      id: GO:0110076
      label: negative regulation of ferroptosis
    evidence_type: IMP
    original_reference_id: PMID:26403645
    review:
      summary: This IMP annotation is based on knockdown experiments in 
        hepatocellular carcinoma cells. PMID:26403645 shows that "Knockdown of 
        p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy 
        chain-1 by RNA interference in HCC cells promoted ferroptosis in 
        response to erastin and sorafenib." FTH1 is transcriptionally activated 
        by NRF2 as part of the antioxidant response.
      action: ACCEPT
      reason: Negative regulation of ferroptosis is a core function of FTH1. By 
        sequestering labile iron, FTH1 limits iron-mediated lipid peroxidation, 
        the hallmark of ferroptosis. This is experimentally validated and 
        physiologically significant.
      supported_by:
        - reference_id: PMID:26403645
          supporting_text: Knockdown of p62, quinone oxidoreductase-1, heme 
            oxygenase-1, and ferritin heavy chain-1 by RNA interference in HCC 
            cells promoted ferroptosis in response to erastin and sorafenib
  - term:
      id: GO:0004322
      label: ferroxidase activity
    evidence_type: IMP
    original_reference_id: PMID:9003196
    review:
      summary: Direct experimental evidence for ferroxidase activity using 
        stopped-flow assays and site-directed mutagenesis. The study 
        demonstrates that "The ferroxidase activity of human ferritin has 
        previously been associated with a diiron site situated centrally within 
        the four-helix bundle of H-type chains (HuHF)."
      action: ACCEPT
      reason: Ferroxidase activity is the defining enzymatic function of FTH1. 
        This IMP annotation is based on rigorous biochemical characterization 
        including kinetic analysis and mutagenesis of the ferroxidase center 
        residues (Glu-28, Lys-87, Glu-108).
      supported_by:
        - reference_id: PMID:9003196
          supporting_text: The ferroxidase activity of human ferritin has 
            previously been associated with a diiron site situated centrally 
            within the four-helix bundle of H-type chains (HuHF)
  - term:
      id: GO:0008198
      label: ferrous iron binding
    evidence_type: IMP
    original_reference_id: PMID:9003196
    review:
      summary: Direct experimental evidence for Fe2+ binding at the ferroxidase 
        center using stopped-flow assays and phenanthroline competition. The 
        study dissected binding and oxidation steps, showing sequential binding 
        at sites A and B.
      action: ACCEPT
      reason: Fe2+ binding is the first step in ferroxidase catalysis and is 
        core to FTH1 function. The IMP evidence from detailed biochemical 
        analysis strongly supports this annotation.
      supported_by:
        - reference_id: PMID:9003196
          supporting_text: the first 48 Fe(II) atoms/molecule added are bound 
            and oxidized at the dinuclear centers
  - term:
      id: GO:0140315
      label: iron ion sequestering activity
    evidence_type: IDA
    original_reference_id: PMID:9924025
    review:
      summary: PMID:9924025 demonstrates that FTH1 sequesters intracellular 
        iron, and that c-MYC represses FTH1 expression to increase the labile 
        iron pool. The study states that H-ferritin "sequesters intracellular 
        iron."
      action: ACCEPT
      reason: Iron ion sequestering activity is the primary molecular function 
        of FTH1. The ferritin nanocage physically sequesters iron atoms within 
        its mineral core, removing them from the reactive labile iron pool. This
        is the functional essence of ferritin.
      supported_by:
        - reference_id: PMID:9924025
          supporting_text: the heavy subunit of the protein ferritin 
            (H-ferritin), which sequesters intracellular iron
  - term:
      id: GO:0044754
      label: autolysosome
    evidence_type: IDA
    original_reference_id: PMID:25327288
    review:
      summary: PMID:25327288 demonstrates that NCOA4 delivers ferritin to 
        autolysosomes for degradation. The study shows that "NCOA4 directly 
        binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin 
        complex... to autolysosomes following starvation or iron depletion."
      action: ACCEPT
      reason: Autolysosomal localization is integral to ferritinophagy and 
        ferritin turnover. This represents a physiologically important 
        trafficking step in iron release.
      supported_by:
        - reference_id: PMID:25327288
          supporting_text: NCOA4 directly binds ferritin heavy chain-1 (FTH1) to
            target the iron-binding ferritin complex with a relative molecular 
            mass of 450,000 to autolysosomes following starvation or iron 
            depletion
  - term:
      id: GO:1904724
      label: tertiary granule lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6798745
    review:
      summary: Reactome pathway annotation for neutrophil degranulation. 
        Ferritin is found in neutrophil tertiary granules and can be released 
        during degranulation.
      action: KEEP_AS_NON_CORE
      reason: Tertiary granule localization in neutrophils represents a 
        cell-type specific localization related to immune function rather than 
        the core iron storage role. This is a valid annotation but peripheral to
        the main function.
  - term:
      id: GO:1904813
      label: ficolin-1-rich granule lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6800434
    review:
      summary: Reactome pathway annotation for neutrophil granule content. 
        Similar to tertiary granule annotation.
      action: KEEP_AS_NON_CORE
      reason: Cell-type specific localization in neutrophil granules. Valid but 
        peripheral to the core iron storage function.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15607035
    review:
      summary: Interaction with hepatitis C virus NS5A protein identified in 
        systematic hepatocellular protein interaction study.
      action: MARK_AS_OVER_ANNOTATED
      reason: Viral protein interaction from host-pathogen study. The 
        significance for normal ferritin function is unclear. Generic protein 
        binding is uninformative.
      supported_by:
        - reference_id: PMID:15607035
          supporting_text: Systematic identification of hepatocellular proteins 
            interacting with NS5A of the hepatitis C virus.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:23533145
    review:
      summary: High-throughput direct assay (HDA) evidence for exosomal 
        localization from proteomics of urinary exosomes in prostatic 
        secretions.
      action: KEEP_AS_NON_CORE
      reason: Exosomal secretion of ferritin has been documented and may 
        contribute to serum ferritin levels and intercellular iron transfer. 
        This is peripheral to the core intracellular iron storage function.
      supported_by:
        - reference_id: PMID:23533145
          supporting_text: 2013 Apr 23. In-depth proteomic analyses of exosomes 
            isolated from expressed prostatic secretions in urine.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: HDA
    original_reference_id: PMID:21630459
    review:
      summary: Nuclear localization detected in sperm nucleus proteomics. The 
        deep research review notes that nuclear FTH1 (nFTH1) in BRCA1/2-mutant 
        breast cancer predicts shorter survival, suggesting nuclear localization
        has biological significance.
      action: KEEP_AS_NON_CORE
      reason: Nuclear localization of FTH1 has been observed in specific 
        contexts and may have prognostic significance in cancer. However, this 
        is not the primary site of ferritin function.
      supported_by:
        - reference_id: PMID:21630459
          supporting_text: Jun 1. Proteomic characterization of the human sperm 
            nucleus.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:19056867
    review:
      summary: Urinary exosome proteomics showing ferritin presence.
      action: KEEP_AS_NON_CORE
      reason: Redundant with other exosome annotation. Exosomal secretion is 
        peripheral to core function.
      supported_by:
        - reference_id: PMID:19056867
          supporting_text: 2008 Dec 3. Large-scale proteomics and 
            phosphoproteomics of urinary exosomes.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6798745
    review:
      summary: Reactome pathway annotation related to neutrophil degranulation 
        and secretion.
      action: KEEP_AS_NON_CORE
      reason: Extracellular ferritin (serum ferritin) is well-documented and 
        clinically important as a biomarker. Secretion occurs via non-classical 
        pathways. This is peripheral to the core intracellular function.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6800434
    review:
      summary: Duplicate annotation for extracellular region from Reactome.
      action: KEEP_AS_NON_CORE
      reason: Same as above - extracellular presence is documented but 
        peripheral to core function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1562626
    review:
      summary: Reactome pathway annotation for ferritin complex oxidizing Fe2+ 
        to Fe3+. Cytosolic localization is consistent with ferritin's primary 
        function site.
      action: ACCEPT
      reason: Cytosolic localization is the primary site of ferritin's iron 
        storage function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-434362
    review:
      summary: Reactome pathway annotation for recruitment of cytoplasmic 
        proteins to vesicles.
      action: ACCEPT
      reason: Cytosolic localization is core to ferritin function.
  - term:
      id: GO:0048147
      label: negative regulation of fibroblast proliferation
    evidence_type: IDA
    original_reference_id: PMID:9924025
    review:
      summary: PMID:9924025 shows that FTH1 expression is repressed by c-MYC, 
        and that "Down-regulation of the expression of H-ferritin gene was 
        required for cell transformation by c-MYC." This indicates FTH1 
        negatively regulates proliferation.
      action: KEEP_AS_NON_CORE
      reason: The anti-proliferative effect of FTH1 is indirect, mediated 
        through iron sequestration reducing the labile iron pool needed for 
        proliferation. This is a downstream consequence rather than a direct 
        molecular function.
      supported_by:
        - reference_id: PMID:9924025
          supporting_text: Down-regulation of the expression of H-ferritin gene 
            was required for cell transformation by c-MYC
  - term:
      id: GO:0006955
      label: immune response
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation based on similarity to UniProtKB:Q8TD27 (FAM81A). 
        The functional relevance of this annotation to FTH1 is unclear. The deep
        research mentions FTH1's role in Treg lineage stability and immune 
        function through iron provision to TET dioxygenases.
      action: KEEP_AS_NON_CORE
      reason: FTH1 does have roles in immune function, particularly in 
        supporting Treg cell stability and iron metabolism in immune cells. 
        However, "immune response" is very broad and the ISS evidence is weak. 
        This is peripheral to core function.
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation similar to the fibroblast proliferation 
        annotation. FTH1's iron sequestration function can limit proliferation 
        by reducing labile iron.
      action: KEEP_AS_NON_CORE
      reason: Anti-proliferative effects are indirect consequences of iron 
        sequestration rather than a direct molecular function of FTH1. The ISS 
        evidence is weak.
  - term:
      id: GO:0005506
      label: iron ion binding
    evidence_type: TAS
    original_reference_id: PMID:3020541
    review:
      summary: TAS annotation from the 1986 paper cloning and characterizing the
        FTH1 gene. Iron binding is fundamental to ferritin function.
      action: MODIFY
      reason: '"Iron ion binding" is accurate but less specific than "ferrous iron
        binding" and "ferric iron binding" which are already annotated. The specific
        annotations are more informative about the mechanistic role.'
      proposed_replacement_terms:
        - id: GO:0008198
          label: ferrous iron binding
        - id: GO:0008199
          label: ferric iron binding
      supported_by:
        - reference_id: PMID:3020541
          supporting_text: Cloning, characterization, expression, and 
            chromosomal localization of a human ferritin heavy-chain gene.
  - term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    evidence_type: TAS
    original_reference_id: PMID:6589621
    review:
      summary: The 1984 paper establishing human ferritin H chain cDNA. States 
        that "Ferritin, the main iron-storage protein" highlighting its central 
        role in iron homeostasis.
      action: ACCEPT
      reason: Intracellular iron ion homeostasis is a core biological process 
        for FTH1. The ferritin system is the primary mechanism for buffering 
        intracellular iron levels.
      supported_by:
        - reference_id: PMID:6589621
          supporting_text: Ferritin, the main iron-storage protein, is composed 
            of two partially homologous subunits, heavy (H) and light (L)
  - term:
      id: GO:0070288
      label: ferritin complex
    evidence_type: TAS
    original_reference_id: PMID:6589621
    review:
      summary: FTH1 is a component of the 24-subunit ferritin complex along with
        FTL. The heteropolymer assembly is well-characterized structurally.
      action: ACCEPT
      reason: Membership in the ferritin complex is essential to FTH1's 
        function. The H and L chains assemble into the iron storage nanocage.
      supported_by:
        - reference_id: PMID:6589621
          supporting_text: Ferritin, the main iron-storage protein, is composed 
            of two partially homologous subunits, heavy (H) and light (L)
core_functions:
  - molecular_function:
      id: GO:0004322
      label: ferroxidase activity
    description: The ferroxidase activity of FTH1 catalyzes oxidation of Fe2+ to
      Fe3+ at the dinuclear center within the four-helix bundle (EC 1.16.3.1). 
      This is the defining enzymatic function of the ferritin heavy chain that 
      enables safe iron storage within the ferritin mineral core.
    directly_involved_in:
      - id: GO:0006879
        label: intracellular iron ion homeostasis
    locations:
      - id: GO:0005829
        label: cytosol
    in_complex:
      id: GO:0070288
      label: ferritin complex
    supported_by:
      - reference_id: PMID:9003196
        supporting_text: The ferroxidase activity of human ferritin has 
          previously been associated with a diiron site situated centrally 
          within the four-helix bundle of H-type chains
  - molecular_function:
      id: GO:0140315
      label: iron ion sequestering activity
    description: FTH1 sequesters intracellular iron by storing it within the 
      ferritin nanocage as an inert ferrihydrite mineral, buffering the labile 
      iron pool and preventing iron-mediated oxidative damage.
    directly_involved_in:
      - id: GO:0006879
        label: intracellular iron ion homeostasis
      - id: GO:0110076
        label: negative regulation of ferroptosis
    locations:
      - id: GO:0005829
        label: cytosol
    in_complex:
      id: GO:0070288
      label: ferritin complex
    supported_by:
      - reference_id: PMID:9924025
        supporting_text: the heavy subunit of the protein ferritin (H-ferritin),
          which sequesters intracellular iron
  - molecular_function:
      id: GO:0008198
      label: ferrous iron binding
    description: FTH1 binds ferrous iron (Fe2+) at the dinuclear ferroxidase 
      center as the first step in the ferroxidase catalytic cycle, with 
      sequential binding at sites A then B.
    locations:
      - id: GO:0005829
        label: cytosol
    in_complex:
      id: GO:0070288
      label: ferritin complex
    supported_by:
      - reference_id: PMID:9003196
        supporting_text: the first 48 Fe(II) atoms/molecule added are bound and 
          oxidized at the dinuclear centers
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:6589621
    title: Isolation and characterization of a cDNA clone for human ferritin 
      heavy chain.
    findings:
      - statement: Established that ferritin is the main iron-storage protein 
          composed of H and L subunits
        supporting_text: Ferritin, the main iron-storage protein, is composed of
          two partially homologous subunits, heavy (H) and light (L)
      - statement: Isolated cDNA clone for human ferritin H chain
        supporting_text: We have isolated a cDNA clone for human ferritin H 
          chains by screening a human lymphocyte cDNA library with synthetic 
          oligodeoxyribonucleotides
  - id: PMID:3020541
    title: Cloning, characterization, expression, and chromosomal localization 
      of a human ferritin heavy-chain gene.
    findings:
      - statement: Characterized the genomic structure of FTH1 with 4 exons 
          spanning ~3 kb
      - statement: Localized the gene to chromosome 11
  - id: PMID:9003196
    title: 'Dinuclear center of ferritin: studies of iron binding and oxidation show
      differences in the two iron sites.'
    findings:
      - statement: Demonstrated ferroxidase activity at the dinuclear center 
          within H-type chains
      - statement: Developed stopped-flow assay to dissect Fe2+ binding and 
          oxidation
      - statement: Showed sequential Fe2+ binding at sites A then B
      - statement: Mutagenesis of Glu-28, Lys-87, Glu-108 affected iron binding 
          and oxidation
  - id: PMID:9924025
    title: Coordinated regulation of iron-controlling genes, H-ferritin and 
      IRP2, by c-MYC.
    findings:
      - statement: c-MYC represses FTH1 expression to increase labile iron pool
      - statement: FTH1 sequesters intracellular iron
      - statement: Down-regulation of FTH1 required for c-MYC-mediated cell 
          transformation
  - id: PMID:24695223
    title: Quantitative proteomics identifies NCOA4 as the cargo receptor 
      mediating ferritinophagy.
    findings:
      - statement: Identified NCOA4 as the selective autophagy receptor for 
          ferritin
      - statement: NCOA4 promotes targeting of ferritin to autolysosomes
  - id: PMID:25327288
    title: Selective VPS34 inhibitor blocks autophagy and uncovers a role for 
      NCOA4 in ferritin degradation and iron homeostasis in vivo.
    findings:
      - statement: NCOA4 directly binds FTH1 to target ferritin to autolysosomes
      - statement: Ferritinophagy occurs following starvation or iron depletion
      - statement: NCOA4 knockout mice accumulate iron in splenic macrophages
  - id: PMID:26403645
    title: Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis
      in hepatocellular carcinoma cells.
    findings:
      - statement: FTH1 is transcriptionally activated by NRF2
      - statement: FTH1 knockdown promotes ferroptosis in response to erastin 
          and sorafenib
      - statement: FTH1 is part of the p62-Keap1-NRF2 ferroptosis defense 
          pathway
  - id: PMID:26436293
    title: Ferritinophagy via NCOA4 is required for erythropoiesis and is 
      regulated by iron dependent HERC2-mediated proteolysis.
    findings:
      - statement: Arg-23 is essential for NCOA4 binding
      - statement: R23A mutation abrogates NCOA4 interaction and lysosomal 
          localization
  - id: Reactome:R-HSA-1562626
    title: Ferritin Complex oxidises 4Fe2+ to Fe(3+)O(OH)
    findings: []
  - id: Reactome:R-HSA-434362
    title: Recruitment Of Cytoplasmic Proteins To Vesicles
    findings: []
  - id: Reactome:R-HSA-6798745
    title: Exocytosis of tertiary granule lumen proteins
    findings: []
  - id: Reactome:R-HSA-6800434
    title: Exocytosis of ficolin-rich granule lumen proteins
    findings: []
  - id: PMID:15607035
    title: Systematic identification of hepatocellular proteins interacting with
      NS5A of the hepatitis C virus.
    findings: []
  - id: PMID:16169070
    title: 'A human protein-protein interaction network: a resource for annotating
      the proteome.'
    findings: []
  - id: PMID:16189514
    title: Towards a proteome-scale map of the human protein-protein interaction
      network.
    findings: []
  - id: PMID:17355907
    title: The TSC1 gene product hamartin interacts with NADE.
    findings: []
  - id: PMID:19056867
    title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
    findings: []
  - id: PMID:20133674
    title: Binding and uptake of H-ferritin are mediated by human transferrin 
      receptor-1.
    findings:
      - statement: H-ferritin binds TfR1 for cellular uptake
  - id: PMID:20195357
    title: A comprehensive resource of interacting protein regions for refining 
      human transcription factor networks.
    findings: []
  - id: PMID:21516116
    title: Next-generation sequencing to generate interactome datasets.
    findings: []
  - id: PMID:21573799
    title: FTH1 binds to Daxx and inhibits Daxx-mediated cell apoptosis.
    findings:
      - statement: FTH1-DAXX interaction inhibits DAXX-mediated apoptosis
  - id: PMID:21630459
    title: Proteomic characterization of the human sperm nucleus.
    findings: []
  - id: PMID:21653829
    title: Protein interactome reveals converging molecular pathways among 
      autism disorders.
    findings: []
  - id: PMID:21988832
    title: Toward an understanding of the protein interaction network of the 
      human liver.
    findings: []
  - id: PMID:22458338
    title: Host-pathogen interactome mapping for HTLV-1 and -2 retroviruses.
    findings: []
  - id: PMID:23533145
    title: In-depth proteomic analyses of exosomes isolated from expressed 
      prostatic secretions in urine.
    findings: []
  - id: PMID:25277244
    title: The functional landscape of Hsp27 reveals new cellular processes such
      as DNA repair and alternative splicing and proposes novel anticancer 
      targets.
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network.
    findings: []
  - id: PMID:25910212
    title: Widespread macromolecular interaction perturbations in human genetic 
      disorders.
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks.
    findings: []
  - id: PMID:31515488
    title: Extensive disruption of protein interactions by genetic variants 
      across the allele frequency spectrum in human populations.
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings: []
  - id: PMID:33087927
    title: Atomic-resolution protein structure determination by cryo-EM.
    findings:
      - statement: High-resolution cryo-EM structure of human ferritin
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional 
      genomics.
    findings: []
  - id: file:human/FTH1/FTH1-deep-research-falcon.md
    title: Deep research report on FTH1
    findings: []
tags:
  - ferroptosis

FTH1

Gene Description

Existing Annotations Review

Core Functions

The ferroxidase activity of FTH1 catalyzes oxidation of Fe2+ to Fe3+ at the dinuclear center within the four-helix bundle (EC 1.16.3.1). This is the defining enzymatic function of the ferritin heavy chain that enables safe iron storage within the ferritin mineral core.

FTH1 sequesters intracellular iron by storing it within the ferritin nanocage as an inert ferrihydrite mineral, buffering the labile iron pool and preventing iron-mediated oxidative damage.

FTH1 binds ferrous iron (Fe2+) at the dinuclear ferroxidase center as the first step in the ferroxidase catalytic cycle, with sequential binding at sites A then B.

References

Tags

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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