Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10211)
Regulator Name Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2)
Synonyms
Autotaxin; Extracellular lysophospholipase D
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Gene Name ENPP2
Gene ID 5168
Regulator Type Protein coding
Uniprot ID Q13822
Sequence
MARRSSFQSCQIISLFTFAVGVNICLGFTAHRIKRAEGWEEGPPTVLSDSPWTNISGSCK
GRCFELQEAGPPDCRCDNLCKSYTSCCHDFDELCLKTARGWECTKDRCGEVRNEENACHC
SEDCLARGDCCTNYQVVCKGESHWVDDDCEEIKAAECPAGFVRPPLIIFSVDGFRASYMK
KGSKVMPNIEKLRSCGTHSPYMRPVYPTKTFPNLYTLATGLYPESHGIVGNSMYDPVFDA
TFHLRGREKFNHRWWGGQPLWITATKQGVKAGTFFWSVVIPHERRILTILQWLTLPDHER
PSVYAFYSEQPDFSGHKYGPFGPEMTNPLREIDKIVGQLMDGLKQLKLHRCVNVIFVGDH
GMEDVTCDRTEFLSNYLTNVDDITLVPGTLGRIRSKFSNNAKYDPKAIIANLTCKKPDQH
FKPYLKQHLPKRLHYANNRRIEDIHLLVERRWHVARKPLDVYKKPSGKCFFQGDHGFDNK
VNSMQTVFVGYGSTFKYKTKVPPFENIELYNVMCDLLGLKPAPNNGTHGSLNHLLRTNTF
RPTMPEEVTRPNYPGIMYLQSDFDLGCTCDDKVEPKNKLDELNKRLHTKGSTEERHLLYG
RPAVLYRTRYDILYHTDFESGYSEIFLMPLWTSYTVSKQAEVSSVPDHLTSCVRPDVRVS
PSFSQNCLAYKNDKQMSYGFLFPPYLSSSPEAKYDAFLVTNMVPMYPAFKRVWNYFQRVL
VKKYASERNGVNVISGPIFDYDYDGLHDTEDKIKQYVEGSSIPVPTHYYSIITSCLDFTQ
PADKCDGPLSVSSFILPHRPDNEESCNSSEDESKWVEELMKMHTARVRDIEHLTSLDFFR
KTSRSYPEILTLKTYLHTYESEI

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Family Nucleotide pyrophosphatase/phosphodiesterase family
Function
Hydrolyzes lysophospholipids to produce the signaling molecule lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Can also act on sphingosylphosphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility-related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development (Probable). Tumor cell motility-stimulating factor. Required for LPA production in activated platelets, cleaves the sn-1 lysophospholipids to generate sn-1 lysophosphatidic acids containing predominantly 18:2 and 20:4 fatty acids. Shows a preference for the sn-1 to the sn-2 isomer of 1-O-alkyl-sn-glycero-3- phosphocholine (lyso-PAF).

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HGNC ID
HGNC:3357
KEGG ID hsa:5168
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
ENPP2 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
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Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]
 Target Info 
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Cardiomyopathy ICD-11: BC43
 Disease Info 
Responsed Drug Doxorubicin Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
Response regulation ENPP2 was transcriptionally regulated by FoxO4 to protect cardiomyocytes from doxorubicin-induced cardiotoxicity by inhibiting ferroptosis. In addition, the inhibitory effects of ENPP2 on Dox-induced ferroptosis were significantly reduced by FoxO4 overexpression, as demonstrated by increased Fe2+ and lipid ROS activity levels, decreased SLC7A11, GPX4 and FPN1 expression, and increased NOX4 expression, which were observed following FoxO4 overexpression.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Suppressor
Responsed Disease Health ICD-11: N.A.
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
Response regulation ENPP2 overexpression causes upregulation of GPX4 in H9c2 cells. In erastin-induced ferroptosis of H9c2 cells, both NRF2 and ACSL4 are increased, whereas ENPP2 overexpression reduces their expression in erastin-treated H9c2 cells.
Nuclear factor erythroid 2-related factor 2 (NFE2L2) [Suppressor; Marker]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Health ICD-11: N.A.
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
Response regulation ENPP2 overexpression causes upregulation of GPX4 in H9c2 cells. In erastin-induced ferroptosis of H9c2 cells, both NRF2 and ACSL4 are increased, whereas ENPP2 overexpression reduces their expression in erastin-treated H9c2 cells.
Long-chain-fatty-acid--CoA ligase 4 (ACSL4) [Driver]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Driver
Responsed Disease Health ICD-11: N.A.
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
Response regulation ENPP2 overexpression causes upregulation of GPX4 in H9c2 cells. In erastin-induced ferroptosis of H9c2 cells, both NRF2 and ACSL4 are increased, whereas ENPP2 overexpression reduces their expression in erastin-treated H9c2 cells.
Cardiomyopathy [ICD-11: BC43]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2) Protein coding
 Regulator Info 
Responsed Drug Doxorubicin Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
Response regulation ENPP2 was transcriptionally regulated by FoxO4 to protect cardiomyocytes from doxorubicin-induced cardiotoxicity by inhibiting ferroptosis. In addition, the inhibitory effects of ENPP2 on Dox-induced ferroptosis were significantly reduced by FoxO4 overexpression, as demonstrated by increased Fe2+ and lipid ROS activity levels, decreased SLC7A11, GPX4 and FPN1 expression, and increased NOX4 expression, which were observed following FoxO4 overexpression.
Health [ICD-11: N.A.]
 Disease Info 
In total 3 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
Response regulation ENPP2 overexpression causes upregulation of GPX4 in H9c2 cells. In erastin-induced ferroptosis of H9c2 cells, both NRF2 and ACSL4 are increased, whereas ENPP2 overexpression reduces their expression in erastin-treated H9c2 cells.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
Response regulation ENPP2 overexpression causes upregulation of GPX4 in H9c2 cells. In erastin-induced ferroptosis of H9c2 cells, both NRF2 and ACSL4 are increased, whereas ENPP2 overexpression reduces their expression in erastin-treated H9c2 cells.
Experiment 3 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
Response regulation ENPP2 overexpression causes upregulation of GPX4 in H9c2 cells. In erastin-induced ferroptosis of H9c2 cells, both NRF2 and ACSL4 are increased, whereas ENPP2 overexpression reduces their expression in erastin-treated H9c2 cells.
Doxorubicin [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Phospholipid hydroperoxide glutathione peroxidase (GPX4) Suppressor
 Target Info 
Responsed Disease Cardiomyopathy ICD-11: BC43
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
Response regulation ENPP2 was transcriptionally regulated by FoxO4 to protect cardiomyocytes from doxorubicin-induced cardiotoxicity by inhibiting ferroptosis. In addition, the inhibitory effects of ENPP2 on Dox-induced ferroptosis were significantly reduced by FoxO4 overexpression, as demonstrated by increased Fe2+ and lipid ROS activity levels, decreased SLC7A11, GPX4 and FPN1 expression, and increased NOX4 expression, which were observed following FoxO4 overexpression.
References
Ref 1 Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicininduced toxicity. Mol Med Rep. 2021 Sep;24(3):668. doi: 10.3892/mmr.2021.12307. Epub 2021 Jul 23.
Ref 2 ENPP2 protects cardiomyocytes from erastin-induced ferroptosis. Biochem Biophys Res Commun. 2018 Apr 30;499(1):44-51. doi: 10.1016/j.bbrc.2018.03.113. Epub 2018 Mar 20.