HEPH Gene

Name	hephaestin
Description	This gene encodes a member of the multicopper oxidase protein family. The encoded protein is involved in the transport of dietary iron from epithelial cells of the intestinal lumen into the circulatory system, and may be involved in copper transport and homeostasis. In mouse, defects in this gene can lead to severe microcytic anemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Hephaestin (HEPH) is a multi‐copper oxidase that plays a central role in cellular iron homeostasis by catalyzing the oxidation of ferrous iron (Fe²⁺) to its ferric form (Fe³⁺), a conversion that is essential for effective iron export and subsequent loading onto transferrin. In the intestine, HEPH is closely coupled with ferroportin on the basolateral membrane of absorptive enterocytes, enabling vectorial export of iron; its localization and association with ferroportin have been demonstrated in fully differentiated human intestinal (Caco‑2) cells, supporting its role in efficient iron efflux (3,10). Although HEPH messenger RNA levels in duodenal tissues appear not to be modulated by iron status per se, its function as a constitutive component of the iron export machinery is underscored by studies in patients with hereditary hemochromatosis, where dysregulation of other iron transporters contrasts with the unaltered expression of HEPH (1). In the central nervous system, genetic ablation of HEPH leads to iron accumulation and increased ferritin levels in multiple brain regions, indicating that HEPH is required to prevent pathological iron deposition (2). Moreover, transcriptional control of HEPH has been implicated in the regulation of cellular iron levels in the gut; for example, the intestinal transcription factor CDX2 directly up‐regulates HEPH expression, which in turn promotes iron export and lowers intracellular iron concentrations—a mechanism that appears relevant in both normal intestinal differentiation and colorectal cancer, where decreased HEPH expression is associated with chemotherapeutic resistance (4,5). In addition, alterations in HEPH expression have been observed in contexts as diverse as HFE modulation in enterocyte models, where HFE expression can lead to a decrease in hephaestin transcripts, and in copper deficiency states—which further emphasizes the interdependence of copper and iron metabolism in maintaining efficient iron export (6,7). Finally, studies in animal models of altered iron absorption, such as the Belgrade rat, show that while compensatory increases in other iron transport genes occur, hephaestin expression may return to baseline under iron‐rich conditions, highlighting its role as a stable component of the iron export system (9). Collectively, these findings support a model in which HEPH functions as an indispensable partner of ferroportin across multiple tissues—ranging from the duodenum and placenta to the brain and tumor microenvironment—to ensure proper oxidation and mobilization of iron, with dysregulation contributing to diverse pathological conditions (1,2,3,4,5,6,7,8,9,10).\n "}]}, {"type": "t", "text": "\n \n <ul>\n <li>"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "</li>\n <li>"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "</li>\n <li>"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "</li>\n <li>"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "</li>\n <li>"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "</li>\n <li>"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "</li>\n <li>"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "</li>\n <li>"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "</li>\n <li>"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "</li>\n <li>"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "</li>\n </ul>"}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andreas Rolfs, Herbert L Bonkovsky, James G Kohlroser, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Intestinal expression of genes involved in iron absorption in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Gastrointest Liver Physiol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpgi.00371.2001"}], "href": "https://doi.org/10.1152/ajpgi.00371.2001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11897618"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11897618"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ruiwei Jiang, Chao Hua, Yike Wan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hephaestin and ceruloplasmin play distinct but interrelated roles in iron homeostasis in mouse brain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Nutr (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3945/jn.114.207316"}], "href": "https://doi.org/10.3945/jn.114.207316"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25788583"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25788583"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Okhee Han, Eun-Young Kim "}, {"type": "b", "children": [{"type": "t", "text": "Colocalization of ferroportin-1 with hephaestin on the basolateral membrane of human intestinal absorptive cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.21392"}], "href": "https://doi.org/10.1002/jcb.21392"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17486601"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17486601"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hong-Wei Zhang, Yi Shi, Ji-Bin Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cancer-associated fibroblast-derived exosomal microRNA-24-3p enhances colon cancer cell resistance to MTX by down-regulating CDX2/HEPH axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.15765"}], "href": "https://doi.org/10.1111/jcmm.15765"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33621425"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33621425"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Takao Hinoi, Galina Gesina, Aytekin Akyol, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Copper deficiency leads to anemia, duodenal hypoxia, upregulation of HIF-2α and altered expression of iron absorption genes in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0059538"}], "href": "https://doi.org/10.1371/journal.pone.0059538"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23555700"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23555700"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jianfa Wu, Li Zhang, Suqin Wu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Hypoxia-inducible factor-2α and iron absorptive gene expression in Belgrade rat intestine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Gastrointest Liver Physiol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpgi.00538.2010"}], "href": "https://doi.org/10.1152/ajpgi.00538.2010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21436314"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21436314"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Yan-Qin Li, Bin Bai, Xiao-Xiao Cao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ferroportin 1 and hephaestin expression in BeWo cell line with different iron treatment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biochem Funct (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cbf.1843"}], "href": "https://doi.org/10.1002/cbf.1843"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22170436"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22170436"}]}]}]}
Synonyms	CPL
Proteins	HEPH_HUMAN
NCBI Gene ID	9843
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

HEPH has 6,579 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 118 datasets.

Click the + buttons to view associations for HEPH from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

HEPH Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of HEPH gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of HEPH gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of HEPH gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of HEPH gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of HEPH gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of HEPH gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of HEPH gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of HEPH gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of HEPH gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of HEPH gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of HEPH gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with HEPH gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with HEPH gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of HEPH gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of HEPH gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of HEPH gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of HEPH gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing HEPH protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing HEPH protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with HEPH protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with HEPH protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of HEPH gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with HEPH gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with HEPH gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with HEPH gene/protein from the curated CTD Gene-Disease Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by HEPH gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with HEPH gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with HEPH gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with HEPH gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with HEPH gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at HEPH gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of HEPH gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of HEPH gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing HEPH from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with HEPH gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with HEPH gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of HEPH gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with HEPH gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.
	GeneSigDB Published Gene Signatures	PubMedIDs of publications reporting gene signatures containing HEPH from the GeneSigDB Published Gene Signatures dataset.
	GEO Signatures of Differentially Expressed Genes for Diseases	disease perturbations changing expression of HEPH gene from the GEO Signatures of Differentially Expressed Genes for Diseases dataset.