Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSES1HA)

• DOT Name: Erythroferrone (ERFE)
• Synonyms: Complement C1q tumor necrosis factor-related protein 15; Myonectin
• Gene Name: ERFE
• Related Disease:
  Chronic kidney disease
  Malaria
  Anemia
  Beta thalassemia
  Beta-thalassemia major
  Childhood myelodysplastic syndrome
  Congenital dyserythropoietic anemia type 1
  Congenital dyserythropoietic anemia type 2
  Coronary atherosclerosis
  Coronary heart disease
  Dehydrated hereditary stomatocytosis
  Fatty liver disease
  Myelodysplastic syndrome
  Myocardial infarction
  Non-insulin dependent diabetes
  Polycythemia vera
  Obesity
  Type-1/2 diabetes
  Chronic renal failure
  Classic Hodgkin lymphoma
  End-stage renal disease
  Huntington disease
  IRIDA syndrome
  Iron-deficiency anemia
  Prediabetes syndrome
• UniProt ID: ERFE_HUMAN
• Sequence:
  MAPARRPAGARLLLVYAGLLAAAAAGLGSPEPGAPSRSRARREPPPGNELPRGPGESRAG
  PAARPPEPTAERAHSVDPRDAWMLFVRQSDKGVNGKKRSRGKAKKLKFGLPGPPGPPGPQ
  GPPGPIIPPEALLKEFQLLLKGAVRQRERAEPEPCTCGPAGPVAASLAPVSATAGEDDDD
  VVGDVLALLAAPLAPGPRAPRVEAAFLCRLRRDALVERRALHELGVYYLPDAEGAFRRGP
  GLNLTSGQYRAPVAGFYALAATLHVALGEPPRRGPPRPRDHLRLLICIQSRCQRNASLEA
  IMGLESSSELFTISVNGVLYLQMGQWTSVFLDNASGCSLTVRSGSHFSAVLLGV
• Function: Iron-regulatory hormone that acts as an erythroid regulator after hemorrhage: produced by erythroblasts following blood loss and mediates suppression of hepcidin (HAMP) expression in the liver, thereby promoting increased iron absorption and mobilization from stores. Promotes lipid uptake into adipocytes and hepatocytes via transcriptional up-regulation of genes involved in fatty acid uptake. Inhibits apoptosis and inflammatory response in cardiomyocytes via promotion of sphingosine-1-phosphate (S1P) and cAMP-dependent activation of AKT signaling. Inhibits autophagy induced by nutrient deficiency in hepatocytes via promoting the phosphorylation of IRS1, AKT, and MTOR, and thereby subsequent activation of the AKT-MTOR signaling pathway. Negatively regulates the differentiation of osteoblasts, potentially via sequestering BMP2, and thereby inhibits the activation of SMAD signaling. The reduction in BMP2 signaling in osteoblasts also results in an increase in expression of the osteoclastogenesis-promoting factors TNFSF11/RANKL and SOST, thereby indirectly promotes bone resorption.

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Biomarker	[1]
Malaria	DISQ9Y50	Definitive	Biomarker	[2]
Anemia	DISTVL0C	Strong	Biomarker	[3]
Beta thalassemia	DIS5RCQK	Strong	Altered Expression	[4]
Beta-thalassemia major	DISW06BV	Strong	Altered Expression	[4]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Genetic Variation	[5]
Congenital dyserythropoietic anemia type 1	DISCBVO6	Strong	Genetic Variation	[6]
Congenital dyserythropoietic anemia type 2	DIS5RDUE	Strong	Altered Expression	[7]
Coronary atherosclerosis	DISKNDYU	Strong	Altered Expression	[8]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[8]
Dehydrated hereditary stomatocytosis	DISGQT6H	Strong	Altered Expression	[9]
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[10]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[5]
Myocardial infarction	DIS655KI	Strong	Biomarker	[11]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[12]
Polycythemia vera	DISB5FPO	Strong	Altered Expression	[13]
Obesity	DIS47Y1K	moderate	Biomarker	[12]
Type-1/2 diabetes	DISIUHAP	Disputed	Biomarker	[14]
Chronic renal failure	DISGG7K6	Limited	Biomarker	[1]
Classic Hodgkin lymphoma	DISV1LU6	Limited	Biomarker	[1]
End-stage renal disease	DISXA7GG	Limited	Biomarker	[1]
Huntington disease	DISQPLA4	Limited	Biomarker	[1]
IRIDA syndrome	DISPN8YW	Limited	Altered Expression	[15]
Iron-deficiency anemia	DIS0VQYF	Limited	Biomarker	[16]
Prediabetes syndrome	DISH2I53	Limited	Biomarker	[17]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Erythroferrone (ERFE).	[18]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Erythroferrone (ERFE).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Erythroferrone (ERFE).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Erythroferrone (ERFE).	[21]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Erythroferrone (ERFE).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Erythroferrone (ERFE).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Erythroferrone (ERFE).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Erythroferrone (ERFE).	[22]

References

• [1] Serum Erythroferrone Levels Associate with Mortality and Cardiovascular Events in Hemodialysis and in CKD Patients: A Two Cohorts Study.J Clin Med. 2019 Apr 16;8(4):523. doi: 10.3390/jcm8040523.
• [2] Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia.Haematologica. 2017 Jan;102(1):60-68. doi: 10.3324/haematol.2016.150227. Epub 2016 Sep 22.
• [3] Hepcidin-25/erythroferrone ratio predicts improvement of anaemia in haemodialysis patients treated with ferric citrate hydrate.Nephrology (Carlton). 2019 Aug;24(8):819-826. doi: 10.1111/nep.13495. Epub 2019 Apr 29.
• [4] Erythroferrone, the new iron regulator: evaluation of its levels in Egyptian patients with beta thalassemia.Ann Hematol. 2020 Jan;99(1):31-39. doi: 10.1007/s00277-019-03882-w. Epub 2019 Dec 13.
• [5] A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome.Sci Transl Med. 2019 Jul 10;11(500):eaav5467. doi: 10.1126/scitranslmed.aav5467.
• [6] Fetal presentation of congenital dyserythropoietic anemia type 1 with novel compound heterozygous CDAN1 mutations.Blood Cells Mol Dis. 2018 Jul;71:63-66. doi: 10.1016/j.bcmd.2018.03.002. Epub 2018 Mar 20.
• [7] The BMP-SMAD pathway mediates the impaired hepatic iron metabolism associated with the ERFE-A260S variant.Am J Hematol. 2019 Nov;94(11):1227-1235. doi: 10.1002/ajh.25613. Epub 2019 Aug 30.
• [8] Higher serum level of CTRP15 in patients with coronary artery disease is associated with disease severity, body mass index and insulin resistance.Arch Physiol Biochem. 2022 Feb;128(1):276-280. doi: 10.1080/13813455.2019.1675713. Epub 2019 Oct 12.
• [9] Gain-of-function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway.Am J Hematol. 2020 Feb;95(2):188-197. doi: 10.1002/ajh.25683. Epub 2019 Dec 9.
• [10] Myonectin deletion promotes adipose fat storage and reduces liver steatosis.FASEB J. 2019 Jul;33(7):8666-8687. doi: 10.1096/fj.201900520R. Epub 2019 Apr 19.
• [11] Myonectin Is an Exercise-Induced Myokine That Protects the Heart From Ischemia-Reperfusion Injury.Circ Res. 2018 Dec 7;123(12):1326-1338. doi: 10.1161/CIRCRESAHA.118.313777.
• [12] Circulating Serum Myonectin Levels in Obesity and Type 2 Diabetes Mellitus.Exp Clin Endocrinol Diabetes. 2021 Jul;129(7):528-534. doi: 10.1055/a-0896-8548. Epub 2019 Jul 24.
• [13] Dysregulated iron metabolism in polycythemia vera: etiology and consequences.Leukemia. 2018 Oct;32(10):2105-2116. doi: 10.1038/s41375-018-0207-9. Epub 2018 Jul 24.
• [14] Plasma Levels of Myonectin But Not Myostatin or Fibroblast-Derived Growth Factor 21 Are Associated with Insulin Resistance in Adult Humans without Diabetes Mellitus.Front Endocrinol (Lausanne). 2018 Jan 31;9:5. doi: 10.3389/fendo.2018.00005. eCollection 2018.
• [15] PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis.J Clin Invest. 2017 May 1;127(5):1786-1797. doi: 10.1172/JCI90519. Epub 2017 Apr 4.
• [16] Erythroferrone and iron status parameters levels in pediatric patients with iron deficiency anemia.Eur J Haematol. 2018 Apr;100(4):356-360. doi: 10.1111/ejh.13021. Epub 2018 Feb 7.
• [17] Myonectin Predicts the Development of Type 2 Diabetes.J Clin Endocrinol Metab. 2018 Jan 1;103(1):139-147. doi: 10.1210/jc.2017-01604.
• [18] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [19] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [20] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [21] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [22] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [23] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [24] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.