FTH1

Summary

FTH1 (ferritin heavy chain 1, HGNC:3976) is a protein-coding gene on chromosome 11q12.3, encoding Ferritin heavy chain (P02794). Stores iron in a soluble, non-toxic, readily available form. It is a selective cancer dependency (DepMap: 53.6% of cell lines).

This gene encodes the heavy subunit of ferritin, the major intracellular iron storage protein in prokaryotes and eukaryotes. It is composed of 24 subunits of the heavy and light ferritin chains. Variation in ferritin subunit composition may affect the rates of iron uptake and release in different tissues. A major function of ferritin is the storage of iron in a soluble and nontoxic state. Defects in ferritin proteins are associated with several neurodegenerative diseases. This gene has multiple pseudogenes. Several alternatively spliced transcript variants have been observed, but their biological validity has not been determined.

Source: NCBI Gene 2495 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegeneration with brain iron accumulation 9 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 27 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 47
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 53.6% of screened cell lines
• MANE Select transcript: NM_002032

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3976
Approved symbol	FTH1
Name	ferritin heavy chain 1
Location	11q12.3
Locus type	gene with protein product
Status	Approved
Aliases	FTH, PLIF, PIG15, FHC
Ensembl gene	ENSG00000167996
Ensembl biotype	protein_coding
OMIM	134770
Entrez	2495

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000273550, ENST00000526640, ENST00000529191, ENST00000529548, ENST00000529631, ENST00000530019, ENST00000532601, ENST00000532829, ENST00000533138, ENST00000534180, ENST00000534719, ENST00000620041, ENST00000897064, ENST00000897065, ENST00000897066, ENST00000897067

RefSeq mRNA: 1 — MANE Select: NM_002032 NM_002032

CCDS: CCDS41655

Canonical transcript exons

ENST00000273550 — 4 exons

Exon	Start	End
ENSE00001408170	61967312	61967634
ENSE00001430448	61964285	61964891
ENSE00003547901	61964987	61965112
ENSE00003566928	61965369	61965515

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 246.7103 / max 2684.3309, expressed in 1827 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120068	217.7469	1826
120067	24.3079	1771
206303	2.1790	916
120066	1.2914	453
206304	1.1032	694
120065	0.0820	40

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.98	gold quality
upper lobe of left lung	UBERON:0008952	99.97	gold quality
nerve	UBERON:0001021	99.96	gold quality
mucosa of stomach	UBERON:0001199	99.96	gold quality
tibial nerve	UBERON:0001323	99.96	gold quality
left coronary artery	UBERON:0001626	99.96	gold quality
right lung	UBERON:0002167	99.96	gold quality
descending thoracic aorta	UBERON:0002345	99.96	gold quality
mucosa of transverse colon	UBERON:0004991	99.96	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.96	gold quality
monocyte	CL:0000576	99.95	gold quality
endocervix	UBERON:0000458	99.95	gold quality
right lobe of thyroid gland	UBERON:0001119	99.95	gold quality
left lobe of thyroid gland	UBERON:0001120	99.95	gold quality
right adrenal gland	UBERON:0001233	99.95	gold quality
left adrenal gland	UBERON:0001234	99.95	gold quality
left uterine tube	UBERON:0001303	99.95	gold quality
ascending aorta	UBERON:0001496	99.95	gold quality
thoracic aorta	UBERON:0001515	99.95	gold quality
right frontal lobe	UBERON:0002810	99.95	gold quality
anterior cingulate cortex	UBERON:0009835	99.95	gold quality
right adrenal gland cortex	UBERON:0035827	99.95	gold quality
rectum	UBERON:0001052	99.94	gold quality
transverse colon	UBERON:0001157	99.94	gold quality
right coronary artery	UBERON:0001625	99.94	gold quality
popliteal artery	UBERON:0002250	99.94	gold quality
small intestine Peyer’s patch	UBERON:0003454	99.94	gold quality
tibial artery	UBERON:0007610	99.94	gold quality
metanephros cortex	UBERON:0010533	99.94	gold quality
ectocervix	UBERON:0012249	99.94	gold quality

Single-cell (SCXA)

Detected in 93 experiment(s), a significant marker in 51.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	108186.84
E-MTAB-8495	yes	97899.73
E-MTAB-9841	yes	72823.21
E-HCAD-8	yes	72822.75
E-GEOD-139324	yes	61150.20
E-CURD-46	yes	56961.25
E-HCAD-15	yes	53930.75
E-MTAB-9067	yes	51471.99
E-MTAB-9435	yes	51386.65
E-GEOD-149689	yes	50793.54
E-MTAB-6653	yes	49609.64
E-CURD-122	yes	45106.79
E-CURD-120	yes	40229.89
E-CURD-126	yes	37834.44
E-MTAB-8530	yes	37540.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1, ATF3, JUN, KAT7, MYC, SP1, TP53

miRNA regulators (miRDB)

33 targeting FTH1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-4724-5P	98.87	67.75	1324
HSA-MIR-3691-5P	98.62	65.88	552
HSA-MIR-518C-5P	98.53	69.20	1640
HSA-MIR-532-5P	98.43	67.53	760
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-1263	98.13	69.18	459
HSA-MIR-6793-3P	97.66	65.78	1084
HSA-MIR-6890-3P	97.50	65.71	997
HSA-MIR-5187-3P	97.28	67.10	1037
HSA-MIR-3116	97.07	65.78	1324
HSA-MIR-514A-5P	96.94	65.49	801

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 53.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• gene coding and flanking regions were sequenced and examined for mutations that might modulate the iron burden of individuals harboring the common mutant hemochromatosis HFE genotype or cause hemochromatosis independent of mutations in the HFE gene (PMID:11783942)
• An alternative model of H ferritin promoter transactivation by c-Jun (H ferritin, also called isoferritin) (PMID:11903046)
• activates regulatory T cells by induction of changes in dendritic cells (PMID:11964300)
• mu-1,2-Peroxobridged di-iron(III) dimer formation in human H-chain ferritin (PMID:11988076)
• Analysis of sequence effect on folding efficiency of ferritin heavy and light subunits. (PMID:12387819)
• FTH expression is mediated by Nrf2 in response to xenobiotics and cancer chemopreventive dithiolethiones (PMID:12435735)
• Placenta immunomodulatory ferritin (PLIF) plays a major role in placentation and embryonic growth. (PMID:14998975)
• Intra-leukocytic hemosiderin inclusions (a complex of ferritin, denatured ferritin and other material) are associated with iron overload and acute infection. (PMID:15727900)
• Data reveal striking differences in iron oxidation and hydrolysis chemistry between human mitochondrial ferritin and human H-chain ferritin despite their similar diiron ferroxidase centers (PMID:15755449)
• H-ferritin mRNA, IL-1beta, and poly(C)-binding proteins may have roles in ferritin translation and iron homeostasis in human liver (PMID:15967798)
• We report the crystallographic structures of four human H apoferritin variants at a resolution of up to 1.5 Angstrom. Crystal derivatives using Zn(II) as redox-stable alternative for Fe(II), allows us to characterize the different metal-binding sites. (PMID:17070541)
• H ferritin regulates folate metabolism through its internal ribosome entry site (PMID:17702748)
• We have detected a significant inverse correlation of -0.565 (P<0.0001) between serum ferritin when <50 microg/L and FGF-23. (PMID:17761032)
• FTL and FTH subunits respond independently to cellular iron concentrations (PMID:18160403)
• C. albicans can exploit iron from host ferritin via morphology dependent binding through Als3 (PMID:19023418)
• ferritin binds to HKa (cleaved high molecular weight kininogen) with high affinity (K(d) 13 nM). Further, ferritin antagonizes the antiangiogenic effects of HKa, enhancing the migration, assembly, and survival of HKa-treated endothelial cells (PMID:19126685)
• human C48-placenta immunoregulatory factor is an effective, single therapeutic agent enabling allogeneic, nonmanipulated murine bone marrow transplantation (PMID:19539693)
• Inhibition of osteoblast activity, mineralization, and specific gene expression is attributed to the ferroxidase activity of ferritin. (PMID:19821764)
• Triple A patients (with known AAAS mutations) lack nuclear FTH1, suggesting that the nuclear translocation of FTH1 is defective. (PMID:19855093)
• Expression of FTL and FTH genes encoding ferretin subunits in lung and renal carcinomas (PMID:20088381)
• This study suggests that there is a relationship between HR and ferritin level, which may be associated with an increased level of oxidative stress. (PMID:20110920)
• TfR1 accounts for most, if not all, of the binding of HFt to mitogen-activated T and B cells, circulating reticulocytes, and all cell lines that we have studied. (PMID:20133674)
• High ferritin is associated with breast cancer. (PMID:20390345)
• transit-site-deficient mutants of human H ferritin, E140A and E140Q, were prepared and their iron oxidation kinetics was analyzed. (PMID:20705053)
• The study shows the facile assembly of mutant FTL and FTH1 subunits into soluble ferritin heteropolymers, but their ability to incorporate iron was significantly reduced relative to wild-type-FTL/FTH1 heteropolymers. (PMID:21029774)
• Results illustrate how silencing H-ferritin can effectively sensitize tumors to chemotherapy. (PMID:21385903)
• results showed the association of secreted IL-10, FHC and iron homoeostasis in Chlamydia trachomatis-infected HeLa-229 cells (PMID:21413929)
• FTH1 is a functional target gene of the BACH1 transcription factor according to ChIP-seq and knockdown analysis in HEK 293 cells. (PMID:21555518)
• FTH1 can inhibit the activation of the JNK signaling pathway and can bind to Daxx, inhibiting Daxx-mediated apoptosis. (PMID:21573799)
• Data provide useful insights into biomineralization of ferritin under in vivo fever conditions as well as in biomimetic synthesis of nanomaterials using ferritin. (PMID:22020807)
• H ferritin silenced human metastatic melanoma cells are characterized by a decreased growth activity, a reduced invasiveness, and a reduced cell adhesion capability. (PMID:22043922)
• There was a positive correlation between reactive oxygen species levels and serum ferritin levels in myelodysplastic syndrome patients (PMID:22117997)
• To study whether the human ferritin heavy chain (FTH1) can be expressed in Hansenula polymorpha, we integrated an expression cassette for FTH1, analyzed the protein expression, and also designed a FTH1-PTH fusion protein. (PMID:22212821)
• Survivin inhibition by an interacting recombinant peptide, derived from the human ferritin heavy chain, impedes tumor cell growth (PMID:22426960)
• Induction of ferritin heavy chain expression results in severe inhibition of apoB-100 secretion from hepatoma cells during HCV infection. (PMID:22443280)
• The hepcidin:ferritin ratio is reduced in relation to increasing fibrosis in chronic liver disease. (PMID:22676252)
• Increased levels of ferritin and decreased total antioxidant status indicated increasing inflammation in chronic hepatitis C. (PMID:22760008)
• Elevated serum ferrin in infants is associated with congenital hypothyroidism. (PMID:22768652)
• H-ferritin overexpression promotes radiation-induced leukemia/lymphoma. (PMID:22843505)
• Increased levels of serum ferritin are adversely associated with cardiac function following myocardial infarction treated with percutaneous coronary intervention. (PMID:23079089)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	fth1b	ENSDARG00000007975
danio_rerio	fth1a	ENSDARG00000015551
mus_musculus	Fth1	ENSMUSG00000024661
rattus_norvegicus		ENSRNOG00000065765
caenorhabditis_elegans		WBGENE00001500
caenorhabditis_elegans	ftn-2	WBGENE00001501

Paralogs (3): FTL (ENSG00000087086), FTHL17 (ENSG00000132446), FTMT (ENSG00000181867)

Protein

Protein identifiers

Ferritin heavy chain — P02794 (reviewed: P02794)

Alternative names: Cell proliferation-inducing gene 15 protein

All UniProt accessions (9): E9PK45, E9PKM5, E9PKY7, E9PPQ4, E9PQR3, E9PRK8, P02794, G3V192, G3V1D1

UniProt curated annotations — full annotation on UniProt →

Function. Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Has ferroxidase activity. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation. Also plays a role in delivery of iron to cells. Mediates iron uptake in capsule cells of the developing kidney. Delivery to lysosomes is mediated by the cargo receptor NCOA4 for autophagic degradation and release of iron.

Subunit / interactions. Oligomer of 24 subunits. There are two types of subunits: L (light) chain and H (heavy) chain. The major chain can be light or heavy, depending on the species and tissue type. In the human liver, the heavy chain is predominant. The functional molecule forms a roughly spherical shell with a diameter of 12 nm and contains a central cavity into which the insoluble mineral iron core is deposited. Interacts with NCOA4; NCOA4 promotes targeting of the iron-binding ferritin complex to autolysosomes following starvation or iron depletion.

Subcellular location. Cytoplasm. Lysosome. Cytoplasmic vesicle. Autophagosome.

Tissue specificity. Expressed in the liver.

Disease relevance. Hemochromatosis 5 (HFE5) [MIM:615517] A disorder of iron metabolism characterized by iron overload. Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading. The disease is caused by variants affecting the gene represented in this entry. In a Japanese family affected by HFE5, a single point mutation has been detected in the iron-responsive element (IRE) in the 5’-UTR of FTH1 mRNA. This mutation leads to an increased binding affinity for iron regulatory protein and thereby to the efficient suppression of mRNA translation. Neurodegeneration with brain iron accumulation 9 (NBIA9) [MIM:620669] An autosomal dominant neurodegenerative disorder associated with iron accumulation, primarily in the basal ganglia. It is characterized by global developmental delay apparent from infancy, and progressive decline of motor and cognitive skills. Clinical features include delayed walking or inability to walk, spasticity with hyperreflexia, ataxia, dystonia, and poor or absent language. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ferritin family.

RefSeq proteins (1): NP_002023* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001519	Ferritin	Family
IPR008331	Ferritin_DPS_dom	Domain
IPR009040	Ferritin-like_diiron	Domain
IPR009078	Ferritin-like_SF	Homologous_superfamily
IPR012347	Ferritin-like	Homologous_superfamily
IPR014034	Ferritin_CS	Conserved_site

Pfam: PF00210

Enzyme classification (BRENDA):

• EC 1.16.3.1 — ferroxidase (BRENDA: 52 organisms, 108 substrates, 62 inhibitors, 161 Km, 41 kcat entries)

Substrate kinetics (BRENDA)

54 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FE2+	0.0006–14.1	29
HYDROQUINONE	0.018–30.5	22
P-PHENYLENEDIAMINE	0.005–1.19	18
FE(II)	0.0006–3.994	14
O2	0.0011–0.0632	10
O-DIANISIDINE	0.12–0.76	5
NADH	0.14–0.23	4
N,N’-DIMETHYL-P-PHENYLENEDIAMINE	0.06–0.164	3
L-EPINEPHRINE	0.0026–5.8	2
O-PHENYLENEDIAMINE	0.0029–4.15	2
2-CHLORO-P-PHENYLENEDIAMINE	0.241	1
2-METHOXY-P-PHENYLENEDIAMINE	0.161	1
2-METHYL-P-PHENYLENEDIAMINE	0.213	1
2-NITRO-P-PHENYLENEDIAMINE	0.0013	1
2-SULFONIC ACID-P-PHENYLENEDIAMINE	0.0026	1

Catalyzed reactions (Rhea), 1 shown:

• 4 Fe(2+) + O2 + 4 H(+) = 4 Fe(3+) + 2 H2O (RHEA:11148)

UniProt features (29 total): helix 6, binding site 6, modified residue 4, mutagenesis site 4, chain 2, turn 2, initiator methionine 1, site 1, sequence conflict 1, strand 1, domain 1

Structure

Experimental structures (PDB)

147 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6B8F	X-RAY DIFFRACTION	1.06
6B8G	X-RAY DIFFRACTION	1.13
7A6A	ELECTRON MICROSCOPY	1.15
8B7O	X-RAY DIFFRACTION	1.17
6WYF	X-RAY DIFFRACTION	1.25
6Z6U	ELECTRON MICROSCOPY	1.25
7RRP	ELECTRON MICROSCOPY	1.27
7A6B	ELECTRON MICROSCOPY	1.33
4Y08	X-RAY DIFFRACTION	1.34
7K3V	ELECTRON MICROSCOPY	1.34
7K3W	ELECTRON MICROSCOPY	1.36
9RGH	X-RAY DIFFRACTION	1.38
4OYN	X-RAY DIFFRACTION	1.43
9RGJ	X-RAY DIFFRACTION	1.5
2CIH	X-RAY DIFFRACTION	1.5
9HQ6	ELECTRON MICROSCOPY	1.51
3AJO	X-RAY DIFFRACTION	1.52
4YKH	X-RAY DIFFRACTION	1.52
8A5N	X-RAY DIFFRACTION	1.52
9W28	X-RAY DIFFRACTION	1.52
9JGP	X-RAY DIFFRACTION	1.53
9RGI	X-RAY DIFFRACTION	1.54
6Z9E	ELECTRON MICROSCOPY	1.55
8PP3	X-RAY DIFFRACTION	1.55
4ZJK	X-RAY DIFFRACTION	1.56
6Z9F	ELECTRON MICROSCOPY	1.56
8A2M	X-RAY DIFFRACTION	1.57
3AJQ	X-RAY DIFFRACTION	1.58
6FTV	X-RAY DIFFRACTION	1.58
7R5O	ELECTRON MICROSCOPY	1.58

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02794-F1	95.69	0.94

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 23 (essential for association with cargo receptor ncoa4)

Ligand- & substrate-binding residues (6): 28; 63; 63; 66; 108; 142

Post-translational modifications (4): 1, 2, 179, 183

Mutagenesis-validated functional residues (4):

Position	Phenotype
23	abrogates interaction with ncoa4. fails to localize to punctate lysosomal structures.
28	reduces iron binding and oxidation rate; when associated with q-87.
87	reduces iron binding and oxidation rate; when associated with a-28. no effect on iron binding but the oxidation rate is
108	no effect on iron binding but the oxidation rate is severely reduced; when associated with q-87.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-3000480	Scavenging by Class A Receptors
R-HSA-432722	Golgi Associated Vesicle Biogenesis
R-HSA-6798695	Neutrophil degranulation
R-HSA-917937	Iron uptake and transport

MSigDB gene sets: 403 (showing top): KOBAYASHI_EGFR_SIGNALING_24HR_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOZGIT_ESR1_TARGETS_DN, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, MODULE_128, HSIAO_HOUSEKEEPING_GENES, REACTOME_MEMBRANE_TRAFFICKING, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN, COLIN_PILOCYTIC_ASTROCYTOMA_VS_GLIOBLASTOMA_UP, GOBP_IRON_ION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_FIBROBLAST_PROLIFERATION, BEIER_GLIOMA_STEM_CELL_DN

GO Biological Process (6): iron ion transport (GO:0006826), intracellular iron ion homeostasis (GO:0006879), immune response (GO:0006955), negative regulation of cell population proliferation (GO:0008285), negative regulation of fibroblast proliferation (GO:0048147), negative regulation of ferroptosis (GO:0110076)

GO Molecular Function (9): ferroxidase activity (GO:0004322), iron ion binding (GO:0005506), ferrous iron binding (GO:0008198), ferric iron binding (GO:0008199), identical protein binding (GO:0042802), iron ion sequestering activity (GO:0140315), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (13): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), autophagosome (GO:0005776), cytosol (GO:0005829), autolysosome (GO:0044754), extracellular exosome (GO:0070062), ferritin complex (GO:0070288), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813), lysosome (GO:0005764), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Binding and Uptake of Ligands by Scavenger Receptors	1
trans-Golgi Network Vesicle Budding	1
Innate Immune System	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
iron ion binding	3
cytoplasm	2
intracellular organelle lumen	2
transition metal ion transport	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
immune system process	1
response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
negative regulation of cell population proliferation	1
fibroblast proliferation	1
regulation of fibroblast proliferation	1
negative regulation of programmed cell death	1
ferroptosis	1
regulation of ferroptosis	1
oxidoreductase activity, acting on metal ions, oxygen as acceptor	1
transition metal ion binding	1
protein binding	1
metal ion sequestering activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
vacuole	1
secondary lysosome	1
extracellular vesicle	1
protein-containing complex	1
tertiary granule	1
ficolin-1-rich granule	1
lytic vacuole	1
intracellular vesicle	1

Protein interactions and networks

STRING

2350 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FTH1	NCOA4	Q13772	989
FTH1	FTL	P02792	983
FTH1	TFRC	P02786	945
FTH1	SLC40A1	Q9NP59	893
FTH1	SLC11A2	P49281	850
FTH1	COX8A	P10176	788
FTH1	MAP3K11	Q16584	785
FTH1	PYGM	P11217	784
FTH1	FKBP2	P26885	779
FTH1	FOSL1	P15407	778
FTH1	AHNAK	Q09666	777
FTH1	SF1	Q15637	768
FTH1	PLCB3	Q01970	767
FTH1	CHRM1	P11229	765
FTH1	ROM1	Q03395	765

IntAct

128 interactions, top by confidence:

A	B	Type	Score
FTL	FTH1	psi-mi:“MI:0915”(physical association)	0.940
FTH1	FTL	psi-mi:“MI:0915”(physical association)	0.940
FTH1	FTL	psi-mi:“MI:0914”(association)	0.940
FTH1	NCOA4	psi-mi:“MI:0914”(association)	0.790
NCOA4	FTL	psi-mi:“MI:0914”(association)	0.790
NCOA4	FTH1	psi-mi:“MI:0915”(physical association)	0.790
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
DAXX	FTH1	psi-mi:“MI:0915”(physical association)	0.690
FTH1	DAXX	psi-mi:“MI:0407”(direct interaction)	0.690
FTH1	DAXX	psi-mi:“MI:0915”(physical association)	0.690
FTH1	FXR2	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (251): FTH1 (Two-hybrid), FTL (Two-hybrid), SDCBP (Two-hybrid), WDYHV1 (Two-hybrid), PCBP1 (Affinity Capture-Western), PCBP2 (Affinity Capture-Western), PCBP1 (Reconstituted Complex), PCBP2 (Reconstituted Complex), PCBP3 (Affinity Capture-Western), FXR2 (Two-hybrid), FTL (Two-hybrid), FTH1 (Two-hybrid), FTH1 (Affinity Capture-Western), ARHGAP1 (Co-fractionation), FTH1 (Affinity Capture-MS)

ESM2 similar proteins: O46119, O46414, O46415, P02791, P02792, P02793, P02794, P07229, P07797, P07798, P08267, P09451, P09528, P0A999, P0A9A1, P17663, P18685, P19130, P19132, P19133, P25319, P25320, P25915, P29389, P29391, P42577, P49946, P49947, P49948, P80145, P85835, P85836, P85837, P85838, P85839, Q26061, Q2MHN1, Q2MHN2, Q2YDI9, Q53VB8

Diamond homologs: A0A7E5WTY7, A0R647, I4DJ24, O46119, O46414, O65100, P02794, P07229, P07797, P07798, P08267, P09528, P17663, P18685, P19130, P19132, P19976, P25319, P25320, P25699, P25915, P29036, P29389, P29390, P41822, P42577, P42578, P49946, P49947, P49948, P80145, P85835, P85836, P85837, P85838, P85839, Q26061, Q2MHN2, Q2YDI9, Q5R8J7

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ATF1	“down-regulates quantity by repression”	FTH1	“transcriptional regulation”
NfKb-p65/p50	“up-regulates quantity by expression”	FTH1	“transcriptional regulation”
FTH1	“form complex”	Ferritin

Disease & clinical

Clinical variants and AI predictions

ClinVar

27 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	7
Likely benign	3
Benign	9

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
16490	NM_002032.3(FTH1):c.-164A>T	Pathogenic
3777009	FTH1, 2-BP DEL, 409TG	Pathogenic
4087751	NM_004183.4(BEST1):c.698del (p.Pro233fs)	Pathogenic
99734	NM_004183.4(BEST1):c.652C>A (p.Arg218Ser)	Likely pathogenic

SpliceAI

857 predictions. Top by Δscore:

Variant	Effect	Δscore
11:61959882:T:TA	acceptor_gain	1.0000
11:61959891:GGT:G	acceptor_gain	1.0000
11:61960041:CAG:C	donor_loss	1.0000
11:61960042:AG:A	donor_loss	1.0000
11:61960043:GGTGT:G	donor_loss	1.0000
11:61960045:T:G	donor_loss	1.0000
11:61962250:TCCA:T	acceptor_loss	1.0000
11:61962253:A:AG	acceptor_gain	1.0000
11:61962253:AGCCT:A	acceptor_gain	1.0000
11:61962254:G:GA	acceptor_gain	1.0000
11:61962254:GC:G	acceptor_gain	1.0000
11:61962254:GCC:G	acceptor_gain	1.0000
11:61962254:GCCT:G	acceptor_gain	1.0000
11:61962254:GCCTG:G	acceptor_gain	1.0000
11:61964887:CACAA:C	acceptor_gain	1.0000
11:61964888:ACAA:A	acceptor_gain	1.0000
11:61964889:CAA:C	acceptor_gain	1.0000
11:61964889:CAAC:C	acceptor_gain	1.0000
11:61964890:AA:A	acceptor_gain	1.0000
11:61964890:AACTG:A	acceptor_loss	1.0000
11:61964891:ACTGC:A	acceptor_loss	1.0000
11:61964892:C:CC	acceptor_gain	1.0000
11:61964892:CT:C	acceptor_loss	1.0000
11:61964895:C:CT	acceptor_gain	1.0000
11:61964900:C:CT	acceptor_gain	1.0000
11:61964978:AATAC:A	donor_loss	1.0000
11:61964979:ATACT:A	donor_loss	1.0000
11:61964980:TAC:T	donor_loss	1.0000
11:61964981:AC:A	donor_loss	1.0000
11:61964982:CTC:C	donor_loss	1.0000

AlphaMissense

1223 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:61965397:C:A	G78V	0.999
11:61967340:A:G	L29P	0.999
11:61964863:A:G	L139P	0.998
11:61965009:G:T	A122D	0.998
11:61965394:C:T	G79D	0.998
11:61965397:C:T	G78D	0.998
11:61965398:C:G	G78R	0.998
11:61965430:G:T	A67D	0.998
11:61965431:C:G	A67P	0.998
11:61965452:A:G	S60P	0.998
11:61965499:C:G	R44P	0.998
11:61964994:T:C	D127G	0.997
11:61964995:C:G	D127H	0.997
11:61965021:A:G	L118P	0.997
11:61965030:A:G	L115P	0.997
11:61965394:C:A	G79V	0.997
11:61965395:C:G	G79R	0.997
11:61965398:C:A	G78C	0.997
11:61965400:C:G	R77P	0.997
11:61965504:A:C	F42L	0.997
11:61965504:A:T	F42L	0.997
11:61965506:A:G	F42L	0.997
11:61967319:A:G	L36P	0.997
11:61967332:A:G	S32P	0.997
11:61964812:A:G	L156S	0.996
11:61964994:T:A	D127V	0.996
11:61964994:T:G	D127A	0.996
11:61965010:C:G	A122P	0.996
11:61965027:A:G	L116P	0.996
11:61965034:A:G	S114P	0.996

dbSNP variants (sampled 300 via entrez): RS1000364569 (11:61967228 G>A), RS1001338219 (11:61967919 C>G,T), RS1001387567 (11:61967278 G>A), RS1002413403 (11:61967213 C>G,T), RS1002431192 (11:61968571 G>C), RS1003289444 (11:61964019 C>T), RS1003731349 (11:61964281 C>A,G), RS1004132998 (11:61968185 G>A), RS1004251296 (11:61966183 A>C), RS1004921950 (11:61967564 C>G,T), RS1005191081 (11:61967754 G>A,C), RS1005748632 (11:61967197 G>A), RS1005781418 (11:61968958 G>A), RS1006037255 (11:61965776 T>C), RS1006331555 (11:61968595 G>A)

Disease associations

OMIM: gene MIM:134770 | disease phenotypes: MIM:615517, MIM:153700, MIM:268000, MIM:193220, MIM:620669, MIM:611809

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration with brain iron accumulation 9	Strong	Autosomal dominant
hemochromatosis type 5	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neurodegeneration with brain iron accumulation 9	Moderate	AD
hemochromatosis type 5	Limited	AD

Mondo (7): hemochromatosis type 5 (MONDO:0014225), vitelliform macular dystrophy 2 (MONDO:0007931), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), autosomal dominant vitreoretinochoroidopathy (MONDO:0008662), neurodegeneration with brain iron accumulation 9 (MONDO:0958012), autosomal recessive bestrophinopathy (MONDO:0012733)

Orphanet (8): FTH1-related iron overload (Orphanet:247790), Best vitelliform macular dystrophy (Orphanet:1243), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Retinitis pigmentosa (Orphanet:791), MRCS syndrome (Orphanet:263347), Autosomal dominant vitreoretinochoroidopathy (Orphanet:3086), Autosomal recessive bestrophinopathy (Orphanet:139455), OBSOLETE: Hemochromatosis type 5 (Orphanet:447792)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001321	Cerebellar hypoplasia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001903	Anemia
HP:0002015	Dysphagia
HP:0002180	Neurodegeneration
HP:0002267	Exaggerated startle response
HP:0002305	Athetosis
HP:0002454	Eye of the tiger anomaly of globus pallidus
HP:0003281	Increased circulating ferritin concentration
HP:0003452	Increased circulating iron concentration
HP:0003577	Congenital onset
HP:0003581	Adult onset
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0008936	Axial hypotonia

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001178_10	Plasma omega-3 polyunsaturated fatty acid level (eicosapentaenoic acid)	2.000000e-08
GCST001179_17	Plasma omega-3 polyunsaturated fatty acid levels (docosapentaenoic acid)	8.000000e-08
GCST001553_6	Estradiol levels	3.000000e-06
GCST002444_5	Plasma omega-6 polyunsaturated fatty acid levels (dihomo-gamma-linolenic acid)	5.000000e-168
GCST002446_1	Plasma omega-6 polyunsaturated fatty acid levels (linoleic acid)	4.000000e-274
GCST002446_7	Plasma omega-6 polyunsaturated fatty acid levels (linoleic acid)	3.000000e-21
GCST002449_6	Plasma omega-6 polyunsaturated fatty acid levels (arachidonic acid)	0.000000e+00
GCST002449_8	Plasma omega-6 polyunsaturated fatty acid levels (arachidonic acid)	7.000000e-147
GCST002450_8	Plasma omega-6 polyunsaturated fatty acid levels (gamma-linolenic acid)	2.000000e-72
GCST012298_15	Schizophrenia, bipolar disorder or major depressive disorder x sex interaction	7.000000e-06
GCST012299_3	Schizophrenia, bipolar disorder or major depressive disorder x sex interaction (3df)	3.000000e-06
GCST012301_5	Schizophrenia, bipolar disorder or major depressive disorder x sex interaction	5.000000e-06
GCST012305_1	Major depressive disorder x sex interaction	2.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007760	eicosapentaenoic acid measurement
EFO:0006809	docosapentaenoic acid measurement
EFO:0004697	estradiol measurement
EFO:0005680	omega-6 polyunsaturated fatty acid measurement
EFO:0008343	sex interaction measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C567518	Bestrophinopathy (supp.)
C565020	Iron Overload, Autosomal Dominant (supp.)
C536352	Vitreoretinochoroidopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066220 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 3 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	(-)-CARYOPHYLLENE OXIDE

PubChem BioAssay actives

1 with measured affinity, of 3 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(1R,4R,6R,10S)-4,12,12-trimethyl-9-methylidene-5-oxatricyclo[8.2.0.04,6]dodecane	2074095: Inhibition of FTH1 (unknown origin)	ic50	0.0010	uM

CTD chemical–gene interactions

241 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, decreases reaction, increases expression, increases reaction (+1 more)	16
Arsenic Trioxide	affects binding, decreases reaction, decreases expression, increases expression, decreases response to substance	9
Tobacco Smoke Pollution	affects expression, increases expression	7
Valproic Acid	affects cotreatment, increases expression, affects expression	7
bisphenol A	affects reaction, increases reaction, affects expression, decreases expression, increases degradation (+2 more)	6
ferrostatin-1	decreases reaction, increases abundance, increases expression, decreases expression	6
Chloroquine	decreases expression, decreases reaction, increases abundance, increases degradation, increases expression (+3 more)	6
Particulate Matter	increases expression, decreases expression, affects expression, increases reaction, increases abundance	6
Deferoxamine	decreases expression, decreases reaction	5
Cadmium Chloride	increases abundance, increases expression	5
methylmercuric chloride	increases expression, affects cotreatment	4
ochratoxin A	increases expression, decreases reaction, decreases expression, increases reaction, affects cotreatment	4
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance, increases oxidation	4
Aerosols	decreases expression, increases expression	3
Antimony Potassium Tartrate	increases expression, decreases expression, increases reaction, affects reaction, decreases reaction (+1 more)	3
Arsenic	decreases reaction, increases abundance, increases expression, affects cotreatment	3
Benzo(a)pyrene	affects cotreatment, increases expression, affects methylation	3
Cadmium	increases abundance, increases expression	3
Carmustine	decreases reaction, increases expression, decreases expression, decreases response to substance	3
Copper	affects binding, increases expression, decreases expression	3
Iron	decreases reaction, increases abundance, increases expression, affects binding, decreases expression	3
Ozone	affects cotreatment, decreases expression, increases oxidation, increases abundance, increases expression	3
Tunicamycin	decreases expression, decreases reaction, increases expression	3
Cyclosporine	increases expression	3
lead acetate	increases expression	2
sodium arsenate	increases abundance, increases expression	2
cinnamaldehyde	increases expression	2
ferric ammonium citrate	increases expression, increases reaction	2
2-tert-butylhydroquinone	affects reaction, decreases reaction, increases expression	2
3-methyladenine	decreases expression, decreases reaction, increases abundance	2

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5513513	Binding	Inhibition of FTH1 (unknown origin)	Targeting autophagy drug discovery: Targets, indications and development trends. — Eur J Med Chem

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2XA	Abcam HEK293T FTH1 KO	Transformed cell line	Female
CVCL_E1NG	HAP1 FTH1 (-) 1	Cancer cell line	Male
CVCL_E1NH	HAP1 FTH1 (-) 2	Cancer cell line	Male
CVCL_E1NI	HAP1 FTH1 (-) 3	Cancer cell line	Male
CVCL_E1NJ	HAP1 FTH1 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

272 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05704088	PHASE4	COMPLETED	SGLT2 Inhibitors Between Reno Protective Effects and Impact on Bone and Mineral Disease Among Lupus Nephritis Patients
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT05457530	PHASE3	WITHDRAWN	Doravirine and Weight Gain in Antiretroviral Naive
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects