General Information of the Ferroptosis Regulator (ID: REG10306)
Regulator Name E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)
Synonyms
HECT-type E3 ubiquitin transferase NED4L; NEDD4.2; Nedd4-2
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Gene Name NEDD4L
Gene ID 23327
Regulator Type Protein coding
Uniprot ID Q96PU5
Sequence
MATGLGEPVYGLSEDEGESRILRVKVVSGIDLAKKDIFGASDPYVKLSLYVADENRELAL
VQTKTIKKTLNPKWNEEFYFRVNPSNHRLLFEVFDENRLTRDDFLGQVDVPLSHLPTEDP
TMERPYTFKDFLLRPRSHKSRVKGFLRLKMAYMPKNGGQDEENSDQRDDMEHGWEVVDSN
DSASQHQEELPPPPLPPGWEEKVDNLGRTYYVNHNNRTTQWHRPSLMDVSSESDNNIRQI
NQEAAHRRFRSRRHISEDLEPEPSEGGDVPEPWETISEEVNIAGDSLGLALPPPPASPGS
RTSPQELSEELSRRLQITPDSNGEQFSSLIQREPSSRLRSCSVTDAVAEQGHLPPPSAPA
GRARSSTVTGGEEPTPSVAYVHTTPGLPSGWEERKDAKGRTYYVNHNNRTTTWTRPIMQL
AEDGASGSATNSNNHLIEPQIRRPRSLSSPTVTLSAPLEGAKDSPVRRAVKDTLSNPQSP
QPSPYNSPKPQHKVTQSFLPPGWEMRIAPNGRPFFIDHNTKTTTWEDPRLKFPVHMRSKT
SLNPNDLGPLPPGWEERIHLDGRTFYIDHNSKITQWEDPRLQNPAITGPAVPYSREFKQK
YDYFRKKLKKPADIPNRFEMKLHRNNIFEESYRRIMSVKRPDVLKARLWIEFESEKGLDY
GGVAREWFFLLSKEMFNPYYGLFEYSATDNYTLQINPNSGLCNEDHLSYFTFIGRVAGLA
VFHGKLLDGFFIRPFYKMMLGKQITLNDMESVDSEYYNSLKWILENDPTELDLMFCIDEE
NFGQTYQVDLKPNGSEIMVTNENKREYIDLVIQWRFVNRVQKQMNAFLEGFTELLPIDLI
KIFDENELELLMCGLGDVDVNDWRQHSIYKNGYCPNHPVIQWFWKAVLLMDAEKRIRLLQ
FVTGTSRVPMNGFAELYGSNGPQLFTIEQWGSPEKLPRAHTCFNRLDLPPYETFEDLREK
LLMAVENAQGFEGVD

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Function
E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins and is thereby implicated in the regulation of various signaling pathways including autophagy, innate immunity or DNA repair. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome- dependent degradation. Downregulates autophagy and cell growth by ubiquitinating and reducing cellular ULK1 or ASCT2 levels. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2, KCNQ3/Kv7.3 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1. Plays a role in dendrite formation by melanocytes. Involved in the regulation of TOR signaling. Ubiquitinates and regulates protein levels of NTRK1 once this one is activated by NGF. Plays a role in antiviral innate immunity by catalyzing 'Lys-29'-linked cysteine ubiquitination of TRAF3, resulting in enhanced 'Lys-48' and 'Lys-63'-linked ubiquitination of TRAF3.

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HGNC ID
HGNC:7728
KEGG ID hsa:23327
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
NEDD4L 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
Browse Drug
Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]
In total 3 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
Responsed Drug Peoniflorin Investigative
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

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Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Suppressor
Responsed Disease Lung cancer ICD-11: 2C25
Responsed Drug Lactate Investigative
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H446 cells Lung small cell carcinoma Homo sapiens CVCL_1562
NCI-H1688 cells Lung small cell carcinoma Homo sapiens CVCL_1487
Response regulation Lactate derived from metabolic reprogramming increases the expression of glutathione peroxidase 4 (GPX4) to promote ferroptosis resistance in Non-Small Cell Lung Cancer (NSCLC). Mechanistically, Lactate increases mitochondrial ROS generation and drives activation of the p38 (MAPK14)-SGK1 pathway, which attenuates the interaction of NEDD4L with GPX4 and subsequent ubiquitination and degradation of GPX4.
Experiment 3 Reporting the Ferroptosis Target of This Regulator [3]
Target for Ferroptosis Suppressor
Responsed Disease Ovarian dysfunction ICD-11: 5A80
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
KGN cells Ovarian granulosa cell tumor Homo sapiens CVCL_0375
In Vivo Model
Adult female C57BL/6J mice were purchased from Cyagen Bioscience (Santa Clara, CA, USA). Prior to the experiment, the animals were allowed to adapt to the environment for 1 week. For this study, all procedures were approved by the Ethics Committee of Shanghai Seventh Peoples Hospital (item number: 2021-AR-059). Adult female C57BL/6J mice were housed withaccess to food and waterad libitum. The PCOS mouse model was established as described previously. In brief, female C57BL/6J mice (4 weeks old) were subcutaneously injected with DHEA (6 mg/0.1kg body weight) daily for 20 days.

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Response regulation NEDD4L facilitates GC ferroptosis by promoting GPX4 ubiquitination and degradation and contributes to the development of polycystic ovary syndrome.
Nuclear factor erythroid 2-related factor 2 (NFE2L2) [Suppressor; Marker]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
Responsed Drug Peoniflorin Investigative
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

    Click to Show/Hide
Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Cystine/glutamate transporter (SLC7A11) [Driver; Suppressor]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [4]
Target for Ferroptosis Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
ZR-75-1 cells Invasive breast carcinoma Homo sapiens CVCL_0588
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Response regulation SLC7A11 expression was regulated by both ESR1 and NEDD4L, in opposite ways. For the first time, the study elucidated that ESR1 and NEDD4L functioned together after radiation treatment and finally induced ferroptosis in breast cancer cells, which provides novel insight into the guidance of clinical treatment of breast cancer.
Unspecific Target [Unspecific Target]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [5]
Responsed Disease Pancreatic cancer ICD-11: 2C10
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
OVCAR-3 cells Ovarian serous adenocarcinoma Homo sapiens CVCL_0465
Response regulation The study screened 571 UPS-related E1, E2, and E3 genes in a human pancreatic cancer cell line (PANC1) and identified the upregulation of NEDD4-like E3 ubiquitin protein ligase (NEDD4L) as a novel ferroptosis suppressor. NEDD4L-mediated LTF protein degradation inhibits intracellular iron accumulation and subsequent oxidative damage-mediated ferroptotic cell death.
Glioblastoma [ICD-11: 2A00]
In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) Protein coding
Responsed Drug Peoniflorin Investigative
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

    Click to Show/Hide
Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) Protein coding
Responsed Drug Peoniflorin Investigative
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

    Click to Show/Hide
Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Lung cancer [ICD-11: 2C25]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) Protein coding
Responsed Drug Lactate Investigative
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H446 cells Lung small cell carcinoma Homo sapiens CVCL_1562
NCI-H1688 cells Lung small cell carcinoma Homo sapiens CVCL_1487
Response regulation Lactate derived from metabolic reprogramming increases the expression of glutathione peroxidase 4 (GPX4) to promote ferroptosis resistance in Non-Small Cell Lung Cancer (NSCLC). Mechanistically, Lactate increases mitochondrial ROS generation and drives activation of the p38 (MAPK14)-SGK1 pathway, which attenuates the interaction of NEDD4L with GPX4 and subsequent ubiquitination and degradation of GPX4.
Breast cancer [ICD-11: 2C60]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [4]
Target Regulator E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) Protein coding
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
ZR-75-1 cells Invasive breast carcinoma Homo sapiens CVCL_0588
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
Response regulation SLC7A11 expression was regulated by both ESR1 and NEDD4L, in opposite ways. For the first time, the study elucidated that ESR1 and NEDD4L functioned together after radiation treatment and finally induced ferroptosis in breast cancer cells, which provides novel insight into the guidance of clinical treatment of breast cancer.
Ovarian dysfunction [ICD-11: 5A80]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) Protein coding
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
KGN cells Ovarian granulosa cell tumor Homo sapiens CVCL_0375
In Vivo Model
Adult female C57BL/6J mice were purchased from Cyagen Bioscience (Santa Clara, CA, USA). Prior to the experiment, the animals were allowed to adapt to the environment for 1 week. For this study, all procedures were approved by the Ethics Committee of Shanghai Seventh Peoples Hospital (item number: 2021-AR-059). Adult female C57BL/6J mice were housed withaccess to food and waterad libitum. The PCOS mouse model was established as described previously. In brief, female C57BL/6J mice (4 weeks old) were subcutaneously injected with DHEA (6 mg/0.1kg body weight) daily for 20 days.

    Click to Show/Hide
Response regulation NEDD4L facilitates GC ferroptosis by promoting GPX4 ubiquitination and degradation and contributes to the development of polycystic ovary syndrome.
Pancreatic cancer [ICD-11: 2C10]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [5]
Target Regulator E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) Protein coding
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
OVCAR-3 cells Ovarian serous adenocarcinoma Homo sapiens CVCL_0465
Response regulation The study screened 571 UPS-related E1, E2, and E3 genes in a human pancreatic cancer cell line (PANC1) and identified the upregulation of NEDD4-like E3 ubiquitin protein ligase (NEDD4L) as a novel ferroptosis suppressor. NEDD4L-mediated LTF protein degradation inhibits intracellular iron accumulation and subsequent oxidative damage-mediated ferroptotic cell death.
Peoniflorin [Investigative]
In total 2 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
Responsed Disease Glioblastoma ICD-11: 2A00
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

    Click to Show/Hide
Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Nuclear factor erythroid 2-related factor 2 (NFE2L2) Suppressor; Marker
Responsed Disease Glioblastoma ICD-11: 2A00
Pathway Response Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
In Vivo Model
U251 cells (6 x 106) were inoculated into the flanks of 4-to 5-week-old athymic nude mice (Shanghai Laboratory Animal Company, Shanghai, China) subcutaneously to generate a subcutaneous xenograft tumor model. After 2 weeks, the tumor model was successfully constructed, the mice were treated single and combined with 100 mg/kg RSL3 (2 times/week) and 1.0 g/kg/days PF. Tumor volumes were measured every 4 days to draw the growth curve. Mice were sacrificed 4 weeks after cell injection. Tumor xenografts were collected, photographed, and weighed and the tumor apoptosis was analyzed by Tunel staining.

    Click to Show/Hide
Response regulation Paeoniflorin (PF) can function as an antitumor agent for glioma treatment by targeting NEDD4L-dependent STAT3 ubiquitination as well as by regulating the Nrf2/GPX4 signaling axis, which might trigger ferroptosis.
Lactate [Investigative]
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [2]
Drug for Ferroptosis Suppressor
Response Target Phospholipid hydroperoxide glutathione peroxidase (GPX4) Suppressor
Responsed Disease Lung cancer ICD-11: 2C25
Pathway Response Fatty acid metabolism hsa01212
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H446 cells Lung small cell carcinoma Homo sapiens CVCL_1562
NCI-H1688 cells Lung small cell carcinoma Homo sapiens CVCL_1487
Response regulation Lactate derived from metabolic reprogramming increases the expression of glutathione peroxidase 4 (GPX4) to promote ferroptosis resistance in Non-Small Cell Lung Cancer (NSCLC). Mechanistically, Lactate increases mitochondrial ROS generation and drives activation of the p38 (MAPK14)-SGK1 pathway, which attenuates the interaction of NEDD4L with GPX4 and subsequent ubiquitination and degradation of GPX4.
References
Ref 1 Paeoniflorin Regulates NEDD4L/STAT3 Pathway to Induce Ferroptosis in Human Glioma Cells. J Oncol. 2022 Dec 28;2022:6093216. doi: 10.1155/2022/6093216. eCollection 2022.
Ref 2 Drug-induced lactate confers ferroptosis resistance via p38-SGK1-NEDD4L-dependent upregulation of GPX4 in NSCLC cells. Cell Death Discov. 2023 May 15;9(1):165. doi: 10.1038/s41420-023-01463-5.
Ref 3 NEDD4L facilitates granulosa cell ferroptosis by promoting GPX4 ubiquitination and degradation. Endocr Connect. 2023 Mar 17;12(4):e220459. doi: 10.1530/EC-22-0459. Print 2023 Apr 1.
Ref 4 The Dual Regulation Effects of ESR1/NEDD4L on SLC7A11 in Breast Cancer Under Ionizing Radiation. Front Cell Dev Biol. 2022 Feb 16;9:772380. doi: 10.3389/fcell.2021.772380. eCollection 2021.
Ref 5 NEDD4L-mediated LTF protein degradation limits ferroptosis. Biochem Biophys Res Commun. 2020 Oct 22;531(4):581-587. doi: 10.1016/j.bbrc.2020.07.032. Epub 2020 Aug 16.