Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10348)
Regulator Name N6-adenosine-methyltransferase non-catalytic subunit (METTL14)
Synonyms
Methyltransferase-like protein 14
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Gene Name METTL14
Gene ID 57721
Regulator Type Protein coding
Uniprot ID Q9HCE5
Sequence
MDSRLQEIRERQKLRRQLLAQQLGAESADSIGAVLNSKDEQREIAETRETCRASYDTSAP
NAKRKYLDEGETDEDKMEEYKDELEMQQDEENLPYEEEIYKDSSTFLKGTQSLNPHNDYC
QHFVDTGHRPQNFIRDVGLADRFEEYPKLRELIRLKDELIAKSNTPPMYLQADIEAFDIR
ELTPKFDVILLEPPLEEYYRETGITANEKCWTWDDIMKLEIDEIAAPRSFIFLWCGSGEG
LDLGRVCLRKWGYRRCEDICWIKTNKNNPGKTKTLDPKAVFQRTKEHCLMGIKGTVKRST
DGDFIHANVDIDLIITEEPEIGNIEKPVEIFHIIEHFCLGRRRLHLFGRDSTIRPGWLTV
GPTLTNSNYNAETYASYFSAPNSYLTGCTEEIERLRPKSPPPKSKSDRGGGAPRGGGRGG
TSAGRGRERNRSNFRGERGGFRGGRGGAHRGGFPPR

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Family MT-A70-like family
Function
The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N(6) position of some mRNAs and regulates the circadian clock, differentiation of embryonic stem cells and cortical neurogenesis. In the heterodimer formed with METTL3, METTL14 constitutes the RNA-binding scaffold that recognizes the substrate rather than the catalytic core. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in mRNA stability and processing. M6A acts as a key regulator of mRNA stability by promoting mRNA destabilization and degradation. In embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency- promoting transcripts results in transcript destabilization. M6A regulates spermatogonial differentiation and meiosis and is essential for male fertility and spermatogenesis. M6A also regulates cortical neurogenesis: m6A methylation of transcripts related to transcription factors, neural stem cells, the cell cycle and neuronal differentiation during brain development promotes their destabilization and decay, promoting differentiation of radial glial cells.

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HGNC ID
HGNC:29330
KEGG ID hsa:57721
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
METTL14 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).
Browse Target
Browse Disease
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Transferrin receptor protein 1 (TFRC) [Driver; Suppressor; Marker]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Cardiomyopathy ICD-11: BC43
 Disease Info 
Responsed Drug Doxorubicin Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 AC16 [Human hybrid cardiomyocyte] cells Normal Homo sapiens CVCL_4U18
In Vivo Model
Male Sprague-Dawley rats (6-8 weeks old; weighed from 210 to 230 g) were purchased from HFK Bioscience Co. Ltd. Rats were randomly assigned to four groups (n = 6 per group). The first was the control group, which were treated daily with 0.5 ml of 0.9% saline by intraperitoneal injection for 14 days, and there were three DOX model groups, which were treated three times weekly with 2.5 mg/kg of DOX by intraperitoneal injection for 14 weeks. At day 14, mice in the DOX model groups were infected through an intramyocardial injection of either control shNC or shMettl14 (1 x 109 titer) at three distinct locations in the left ventricular free wall three times a week for 2 weeks, and they were treated daily with 30 mg/kg of ferroptosis inducer erastin (MedChemExpress, USA) through intragastric administration or vehicle control (Saline) for 2 weeks.

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Response regulation Doxorubicin treatment resulted in the upregulation of methyltransferase-like 14 (METTL14), which catalyzes the m6A modification of the long non-coding RNA KCNQ1OT1, a miR-7-5p sponge. And miR-7-5p inhibits DOX-induced ferroptosis in cardiomyocytes by directly repressing TFRC. Inhibiting ferroptosis mediated by a METTL14/KCNQ1OT1/miR-7-5p positive feedback loop in cardiomyocytes could provide a new therapeutic approach to control DOX-induced cardiac injury.
Unspecific Target [Unspecific Target]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Responsed Disease Cardiomyopathy ICD-11: BC43
 Disease Info 
Responsed Drug Doxorubicin Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 AC16 [Human hybrid cardiomyocyte] cells Normal Homo sapiens CVCL_4U18
In Vivo Model
Male Sprague-Dawley rats (6-8 weeks old; weighed from 210 to 230 g) were purchased from HFK Bioscience Co. Ltd. Rats were randomly assigned to four groups (n = 6 per group). The first was the control group, which were treated daily with 0.5 ml of 0.9% saline by intraperitoneal injection for 14 days, and there were three DOX model groups, which were treated three times weekly with 2.5 mg/kg of DOX by intraperitoneal injection for 14 weeks. At day 14, mice in the DOX model groups were infected through an intramyocardial injection of either control shNC or shMettl14 (1 x 109 titer) at three distinct locations in the left ventricular free wall three times a week for 2 weeks, and they were treated daily with 30 mg/kg of ferroptosis inducer erastin (MedChemExpress, USA) through intragastric administration or vehicle control (Saline) for 2 weeks.

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Response regulation The RNA-binding protein IGF2BP1 is associated with KCNQ1OT1 to increase its stability and robustly inhibit miR-7-5p activity. MiR-7-5p could effectively suppress METLL14 and TFRC expression. The study suggested a therapeutic strategy to alleviate doxorubicin (DOX)-induced cardiomyopathy.
Cystine/glutamate transporter (SLC7A11) [Driver; Suppressor]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Suppressor
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Glutamate metabolism hsa00250
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
HCCLM3 cells Adult hepatocellular carcinoma Homo sapiens CVCL_6832
MHCC97-H cells Adult hepatocellular carcinoma Homo sapiens CVCL_4972
PLC/PRF/5 cells Hepatocellular carcinoma Homo sapiens CVCL_0485
BEL-7402 cells Endocervical adenocarcinoma Homo sapiens CVCL_5492
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
In Vivo Model
The BALB/C nude mice were obtained from Shanghai SLAC Laboratory Animal Co., Ltd. 5 x 105 stable SLC7A11-knockdown HCCLM3 cells or SLC7A11-vector cells were injected subcutaneously into BALB/C nude mice. After 5 weeks, mice were killed, and tumour photograph was detected with photography. In the other animal work, 5 x 105 stable METTL14-vector HCCLM3 cells, SLC7A11-Overexpression cells or SLC7A11-R298P cells were injected subcutaneously into BALB/C nude mice.

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Response regulation METTL14 induced m6A modification at 5'UTR of SLC7A11 mRNA, which in turn underwent degradation relied on the YTHDF2-dependent pathway. Importantly, ectopic expression of SLC7A11 strongly blocked METTL14-induced tumour-suppressive effect in hypoxic hepatocellular carcinoma.
Cardiomyopathy [ICD-11: BC43]
 Disease Info 
In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator N6-adenosine-methyltransferase non-catalytic subunit (METTL14) Protein coding
 Regulator Info 
Responsed Drug Doxorubicin Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 AC16 [Human hybrid cardiomyocyte] cells Normal Homo sapiens CVCL_4U18
In Vivo Model
Male Sprague-Dawley rats (6-8 weeks old; weighed from 210 to 230 g) were purchased from HFK Bioscience Co. Ltd. Rats were randomly assigned to four groups (n = 6 per group). The first was the control group, which were treated daily with 0.5 ml of 0.9% saline by intraperitoneal injection for 14 days, and there were three DOX model groups, which were treated three times weekly with 2.5 mg/kg of DOX by intraperitoneal injection for 14 weeks. At day 14, mice in the DOX model groups were infected through an intramyocardial injection of either control shNC or shMettl14 (1 x 109 titer) at three distinct locations in the left ventricular free wall three times a week for 2 weeks, and they were treated daily with 30 mg/kg of ferroptosis inducer erastin (MedChemExpress, USA) through intragastric administration or vehicle control (Saline) for 2 weeks.

    Click to Show/Hide
Response regulation Doxorubicin treatment resulted in the upregulation of methyltransferase-like 14 (METTL14), which catalyzes the m6A modification of the long non-coding RNA KCNQ1OT1, a miR-7-5p sponge. And miR-7-5p inhibits DOX-induced ferroptosis in cardiomyocytes by directly repressing TFRC. Inhibiting ferroptosis mediated by a METTL14/KCNQ1OT1/miR-7-5p positive feedback loop in cardiomyocytes could provide a new therapeutic approach to control DOX-induced cardiac injury.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator N6-adenosine-methyltransferase non-catalytic subunit (METTL14) Protein coding
 Regulator Info 
Responsed Drug Doxorubicin Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 AC16 [Human hybrid cardiomyocyte] cells Normal Homo sapiens CVCL_4U18
In Vivo Model
Male Sprague-Dawley rats (6-8 weeks old; weighed from 210 to 230 g) were purchased from HFK Bioscience Co. Ltd. Rats were randomly assigned to four groups (n = 6 per group). The first was the control group, which were treated daily with 0.5 ml of 0.9% saline by intraperitoneal injection for 14 days, and there were three DOX model groups, which were treated three times weekly with 2.5 mg/kg of DOX by intraperitoneal injection for 14 weeks. At day 14, mice in the DOX model groups were infected through an intramyocardial injection of either control shNC or shMettl14 (1 x 109 titer) at three distinct locations in the left ventricular free wall three times a week for 2 weeks, and they were treated daily with 30 mg/kg of ferroptosis inducer erastin (MedChemExpress, USA) through intragastric administration or vehicle control (Saline) for 2 weeks.

    Click to Show/Hide
Response regulation The RNA-binding protein IGF2BP1 is associated with KCNQ1OT1 to increase its stability and robustly inhibit miR-7-5p activity. MiR-7-5p could effectively suppress METLL14 and TFRC expression. The study suggested a therapeutic strategy to alleviate doxorubicin (DOX)-induced cardiomyopathy.
Hepatocellular carcinoma [ICD-11: 2C12]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator N6-adenosine-methyltransferase non-catalytic subunit (METTL14) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Glutamate metabolism hsa00250
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
HCCLM3 cells Adult hepatocellular carcinoma Homo sapiens CVCL_6832
MHCC97-H cells Adult hepatocellular carcinoma Homo sapiens CVCL_4972
PLC/PRF/5 cells Hepatocellular carcinoma Homo sapiens CVCL_0485
BEL-7402 cells Endocervical adenocarcinoma Homo sapiens CVCL_5492
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
In Vivo Model
The BALB/C nude mice were obtained from Shanghai SLAC Laboratory Animal Co., Ltd. 5 x 105 stable SLC7A11-knockdown HCCLM3 cells or SLC7A11-vector cells were injected subcutaneously into BALB/C nude mice. After 5 weeks, mice were killed, and tumour photograph was detected with photography. In the other animal work, 5 x 105 stable METTL14-vector HCCLM3 cells, SLC7A11-Overexpression cells or SLC7A11-R298P cells were injected subcutaneously into BALB/C nude mice.

    Click to Show/Hide
Response regulation METTL14 induced m6A modification at 5'UTR of SLC7A11 mRNA, which in turn underwent degradation relied on the YTHDF2-dependent pathway. Importantly, ectopic expression of SLC7A11 strongly blocked METTL14-induced tumour-suppressive effect in hypoxic hepatocellular carcinoma.
Doxorubicin [Investigative]
 Drug Info 
In total 2 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Transferrin receptor protein 1 (TFRC) Driver; Suppressor; Marker
 Target Info 
Responsed Disease Cardiomyopathy ICD-11: BC43
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 AC16 [Human hybrid cardiomyocyte] cells Normal Homo sapiens CVCL_4U18
In Vivo Model
Male Sprague-Dawley rats (6-8 weeks old; weighed from 210 to 230 g) were purchased from HFK Bioscience Co. Ltd. Rats were randomly assigned to four groups (n = 6 per group). The first was the control group, which were treated daily with 0.5 ml of 0.9% saline by intraperitoneal injection for 14 days, and there were three DOX model groups, which were treated three times weekly with 2.5 mg/kg of DOX by intraperitoneal injection for 14 weeks. At day 14, mice in the DOX model groups were infected through an intramyocardial injection of either control shNC or shMettl14 (1 x 109 titer) at three distinct locations in the left ventricular free wall three times a week for 2 weeks, and they were treated daily with 30 mg/kg of ferroptosis inducer erastin (MedChemExpress, USA) through intragastric administration or vehicle control (Saline) for 2 weeks.

    Click to Show/Hide
Response regulation Doxorubicin treatment resulted in the upregulation of methyltransferase-like 14 (METTL14), which catalyzes the m6A modification of the long non-coding RNA KCNQ1OT1, a miR-7-5p sponge. And miR-7-5p inhibits DOX-induced ferroptosis in cardiomyocytes by directly repressing TFRC. Inhibiting ferroptosis mediated by a METTL14/KCNQ1OT1/miR-7-5p positive feedback loop in cardiomyocytes could provide a new therapeutic approach to control DOX-induced cardiac injury.
Experiment 2 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Unspecific Target
Responsed Disease Cardiomyopathy ICD-11: BC43
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 AC16 [Human hybrid cardiomyocyte] cells Normal Homo sapiens CVCL_4U18
In Vivo Model
Male Sprague-Dawley rats (6-8 weeks old; weighed from 210 to 230 g) were purchased from HFK Bioscience Co. Ltd. Rats were randomly assigned to four groups (n = 6 per group). The first was the control group, which were treated daily with 0.5 ml of 0.9% saline by intraperitoneal injection for 14 days, and there were three DOX model groups, which were treated three times weekly with 2.5 mg/kg of DOX by intraperitoneal injection for 14 weeks. At day 14, mice in the DOX model groups were infected through an intramyocardial injection of either control shNC or shMettl14 (1 x 109 titer) at three distinct locations in the left ventricular free wall three times a week for 2 weeks, and they were treated daily with 30 mg/kg of ferroptosis inducer erastin (MedChemExpress, USA) through intragastric administration or vehicle control (Saline) for 2 weeks.

    Click to Show/Hide
Response regulation The RNA-binding protein IGF2BP1 is associated with KCNQ1OT1 to increase its stability and robustly inhibit miR-7-5p activity. MiR-7-5p could effectively suppress METLL14 and TFRC expression. The study suggested a therapeutic strategy to alleviate doxorubicin (DOX)-induced cardiomyopathy.
References
Ref 1 METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis. Cell Biol Toxicol. 2023 Jun;39(3):1015-1035. doi: 10.1007/s10565-021-09660-7. Epub 2021 Oct 14.
Ref 2 Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2-dependent silencing of SLC7A11. J Cell Mol Med. 2021 Nov;25(21):10197-10212. doi: 10.1111/jcmm.16957. Epub 2021 Oct 5.