Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10187)
Regulator Name Neutrophil gelatinase-associated lipocalin (LCN2)
Synonyms
HNL, NGAL ; 25 kDa alpha-2-microglobulin-related subunit of MMP-9; p25
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Gene Name LCN2
Gene ID 3934
Regulator Type Protein coding
Uniprot ID P80188
Sequence
MPLGLLWLGLALLGALHAQAQDSTSDLIPAPPLSKVPLQQNFQDNQFQGKWYVVGLAGNA
ILREDKDPQKMYATIYELKEDKSYNVTSVLFRKKKCDYWIRTFVPGCQPGEFTLGNIKSY
PGLTSYLVRVVSTNYNQHAMVFFKKVSQNREYFKITLYGRTKELTSELKENFIRFSKSLG
LPENHIVFPVPIDQCIDG

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Family Lipocalin family
Function
Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development. Binds iron through association with 2,3-dihydroxybenzoic acid (2,3-DHBA), a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell, depending on the context. Iron-bound form (holo-24p3) is internalized following binding to the SLC22A17 (24p3R) receptor, leading to release of iron and subsequent increase of intracellular iron concentration. In contrast, association of the iron- free form (apo-24p3) with the SLC22A17 (24p3R) receptor is followed by association with an intracellular siderophore, iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration. Involved in apoptosis due to interleukin-3 (IL3) deprivation: iron-loaded form increases intracellular iron concentration without promoting apoptosis, while iron-free form decreases intracellular iron levels, inducing expression of the proapoptotic protein BCL2L11/BIM, resulting in apoptosis. Involved in innate immunity; limits bacterial proliferation by sequestering iron bound to microbial siderophores, such as enterobactin. Can also bind siderophores from M.tuberculosis.

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HGNC ID
HGNC:6526
KEGG ID hsa:3934
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
LCN2 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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4F2 cell-surface antigen heavy chain (SLC3A2) [Suppressor]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Intracerebral hemorrhage ICD-11: 8B00
 Disease Info 
Responsed Drug Dihydromyricetin Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 hBCs (Brain cells)
In Vivo Model
Male C57BL/6 mice, aged 8-10 weeks and weighing 22-25 g, were purchased from the Hubei Provincial Center for Disease Control and Prevention in Wuhan, China. Mice were initially administered with 1% sodium pentobarbital (70 mg/kg; Sinopharm Chemical Agent Co., Ltd., Shanghai, China) intraperitoneally. Subsequently, they were secured on a stereotaxic device (RWD Life Science Co., Shenzhen). 0.6 ul of collagenase (1 ku/ml) was injected into the caudate nucleus of the mice (bregma 0: 0.5 mm anterior, 2 mm left lateral and 3.5 mm deep) with the help of a brain stereotactic sampling needle (Hamilton).

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Response regulation Dihydromyricetin (DMY) may attenuate symptoms of intracerebral hemorrhage (ICH) in mice, and its potential mechanisms are closely linked to LCN2/system Xc-. The ICH-induced augmentation of LCN2 expression leads to the formation of LCN2-SLC3A2 complexes, which suppress the transport activity of system Xc- and result in the accumulation of ROS and the emergence of ferroptosis.
Unspecific Target [Unspecific Target]
In total 3 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
NF-kappa B signaling pathway hsa04064
Cell Process Cell ferroptosis
In Vitro Model
 Royan N9 cells Normal Mus musculus CVCL_9455
Royan N33 cells Normal Mus musculus CVCL_9417
T98 cells Glioblastoma Homo sapiens CVCL_B368
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
LN-229 cells Glioblastoma Homo sapiens CVCL_0393
A-172 cells Glioblastoma Homo sapiens CVCL_0131
U118 cells Astrocytoma Homo sapiens CVCL_0633
In Vivo Model
Four-to five-week-old female BALB/c nude mice were obtained from the Laboratory Animal Center, Southern Medical University. To study the role of IRP1 in TMZ resistance, the mice were randomly divided into four groups (n = 6 per group) (U87TR, U87TR + TMZ, U87TR-lvIRP1, U87TR-lvIRP1 + TMZ). To establish the GBM models, IRP1 overexpress or control U87TR cells (5 x 105 cells per mice in 3 uL PBS) transfected with luciferase lentivirus were injected into the mice brain under the guidance of a stereotactic instrument at coordinates relative to bregma: 2.0 mm posterior, 2.0 mm lateral, and 3.0 mm ventral.

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Response regulation Amplifying IRP1 signals can reverse TMZ resistance and suppress tumor growthin vivo via inhibiting NFKB2 in the noncanonical NF-B signaling pathway. In addition, NFKB2 affected TMZ sensitivity of glioblastoma by modulating the expression of LCN2 and FPN1 in glioblastoma.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [3]
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 HEK-293T cells Normal Homo sapiens CVCL_0063
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Mahlavu cells Hepatoma Homo sapiens CVCL_0405
PLC/PRF/5 cells Hepatocellular carcinoma Homo sapiens CVCL_0485
HA22T/VGH cells Hepatocellular carcinoma Homo sapiens CVCL_7046
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
In Vivo Model
PDX tumors in cold Dulbeccos Modified Eagles Medium (DMEM) were minced into 1-2 mm3 fragments, and each fragment was subcutaneously transplanted into the dorsal flank of 6-week-old male NSG (non-obese diabetic; severe combined immunodeficiency; interleukin-2 receptor gamma chain null) mice. Tumor growth was monitored by bidimensional tumor measurements with a caliper twice a week until the endpoint.

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Response regulation LIFR and SHP1 (PTPN6) positively regulate ferroptosis while LCN2 negatively regulates ferroptosis. Notably, an LCN2 -neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on hepatocellular carcinoma patient-derived xenograft tumors with low LIFR expression and high LCN2 expression.
Experiment 3 Reporting the Ferroptosis Target of This Regulator [4]
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
 MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
ZR-75-30 cells Breast carcinoma Homo sapiens CVCL_1661
T-47D cells Invasive breast carcinoma Homo sapiens CVCL_0553
BT-549 cells Invasive breast carcinoma Homo sapiens CVCL_1092
MCF-10A cells Normal Homo sapiens CVCL_0598
Response regulation WTAP knockdown promoted ferroptosis to suppress triple-negative breast cancer (TNBC) cell malignant behaviors, which were abrogated by NUPR1 overexpression. WTAP upregulated LCN2 by regulation of NUPR1 m6A modification, thereby suppressing ferroptosis to contribute to accelerate TNBC progression.
Intracerebral hemorrhage [ICD-11: 8B00]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Neutrophil gelatinase-associated lipocalin (LCN2) Protein coding
 Regulator Info 
Responsed Drug Dihydromyricetin Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 hBCs (Brain cells)
In Vivo Model
Male C57BL/6 mice, aged 8-10 weeks and weighing 22-25 g, were purchased from the Hubei Provincial Center for Disease Control and Prevention in Wuhan, China. Mice were initially administered with 1% sodium pentobarbital (70 mg/kg; Sinopharm Chemical Agent Co., Ltd., Shanghai, China) intraperitoneally. Subsequently, they were secured on a stereotaxic device (RWD Life Science Co., Shenzhen). 0.6 ul of collagenase (1 ku/ml) was injected into the caudate nucleus of the mice (bregma 0: 0.5 mm anterior, 2 mm left lateral and 3.5 mm deep) with the help of a brain stereotactic sampling needle (Hamilton).

    Click to Show/Hide
Response regulation Dihydromyricetin (DMY) may attenuate symptoms of intracerebral hemorrhage (ICH) in mice, and its potential mechanisms are closely linked to LCN2/system Xc-. The ICH-induced augmentation of LCN2 expression leads to the formation of LCN2-SLC3A2 complexes, which suppress the transport activity of system Xc- and result in the accumulation of ROS and the emergence of ferroptosis.
Glioblastoma [ICD-11: 2A00]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Neutrophil gelatinase-associated lipocalin (LCN2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
NF-kappa B signaling pathway hsa04064
Cell Process Cell ferroptosis
In Vitro Model
 Royan N9 cells Normal Mus musculus CVCL_9455
Royan N33 cells Normal Mus musculus CVCL_9417
T98 cells Glioblastoma Homo sapiens CVCL_B368
U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
LN-229 cells Glioblastoma Homo sapiens CVCL_0393
A-172 cells Glioblastoma Homo sapiens CVCL_0131
U118 cells Astrocytoma Homo sapiens CVCL_0633
In Vivo Model
Four-to five-week-old female BALB/c nude mice were obtained from the Laboratory Animal Center, Southern Medical University. To study the role of IRP1 in TMZ resistance, the mice were randomly divided into four groups (n = 6 per group) (U87TR, U87TR + TMZ, U87TR-lvIRP1, U87TR-lvIRP1 + TMZ). To establish the GBM models, IRP1 overexpress or control U87TR cells (5 x 105 cells per mice in 3 uL PBS) transfected with luciferase lentivirus were injected into the mice brain under the guidance of a stereotactic instrument at coordinates relative to bregma: 2.0 mm posterior, 2.0 mm lateral, and 3.0 mm ventral.

    Click to Show/Hide
Response regulation Amplifying IRP1 signals can reverse TMZ resistance and suppress tumor growthin vivo via inhibiting NFKB2 in the noncanonical NF-B signaling pathway. In addition, NFKB2 affected TMZ sensitivity of glioblastoma by modulating the expression of LCN2 and FPN1 in glioblastoma.
Hepatocellular carcinoma [ICD-11: 2C12]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator Neutrophil gelatinase-associated lipocalin (LCN2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 HEK-293T cells Normal Homo sapiens CVCL_0063
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Mahlavu cells Hepatoma Homo sapiens CVCL_0405
PLC/PRF/5 cells Hepatocellular carcinoma Homo sapiens CVCL_0485
HA22T/VGH cells Hepatocellular carcinoma Homo sapiens CVCL_7046
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
In Vivo Model
PDX tumors in cold Dulbeccos Modified Eagles Medium (DMEM) were minced into 1-2 mm3 fragments, and each fragment was subcutaneously transplanted into the dorsal flank of 6-week-old male NSG (non-obese diabetic; severe combined immunodeficiency; interleukin-2 receptor gamma chain null) mice. Tumor growth was monitored by bidimensional tumor measurements with a caliper twice a week until the endpoint.

    Click to Show/Hide
Response regulation LIFR and SHP1 (PTPN6) positively regulate ferroptosis while LCN2 negatively regulates ferroptosis. Notably, an LCN2 -neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on hepatocellular carcinoma patient-derived xenograft tumors with low LIFR expression and high LCN2 expression.
Breast cancer [ICD-11: 2C60]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [4]
Target Regulator Neutrophil gelatinase-associated lipocalin (LCN2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
Cell invasion
In Vitro Model
 MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
ZR-75-30 cells Breast carcinoma Homo sapiens CVCL_1661
T-47D cells Invasive breast carcinoma Homo sapiens CVCL_0553
BT-549 cells Invasive breast carcinoma Homo sapiens CVCL_1092
MCF-10A cells Normal Homo sapiens CVCL_0598
Response regulation WTAP knockdown promoted ferroptosis to suppress triple-negative breast cancer (TNBC) cell malignant behaviors, which were abrogated by NUPR1 overexpression. WTAP upregulated LCN2 by regulation of NUPR1 m6A modification, thereby suppressing ferroptosis to contribute to accelerate TNBC progression.
Dihydromyricetin [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Suppressor
Response Target 4F2 cell-surface antigen heavy chain (SLC3A2) Suppressor
 Target Info 
Responsed Disease Intracerebral hemorrhage ICD-11: 8B00
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 hBCs (Brain cells)
In Vivo Model
Male C57BL/6 mice, aged 8-10 weeks and weighing 22-25 g, were purchased from the Hubei Provincial Center for Disease Control and Prevention in Wuhan, China. Mice were initially administered with 1% sodium pentobarbital (70 mg/kg; Sinopharm Chemical Agent Co., Ltd., Shanghai, China) intraperitoneally. Subsequently, they were secured on a stereotaxic device (RWD Life Science Co., Shenzhen). 0.6 ul of collagenase (1 ku/ml) was injected into the caudate nucleus of the mice (bregma 0: 0.5 mm anterior, 2 mm left lateral and 3.5 mm deep) with the help of a brain stereotactic sampling needle (Hamilton).

    Click to Show/Hide
Response regulation Dihydromyricetin (DMY) may attenuate symptoms of intracerebral hemorrhage (ICH) in mice, and its potential mechanisms are closely linked to LCN2/system Xc-. The ICH-induced augmentation of LCN2 expression leads to the formation of LCN2-SLC3A2 complexes, which suppress the transport activity of system Xc- and result in the accumulation of ROS and the emergence of ferroptosis.
References
Ref 1 Dihydromyricetin attenuates intracerebral hemorrhage by reversing the effect of LCN2 via the system Xc- pathway. Phytomedicine. 2023 Jul;115:154756. doi: 10.1016/j.phymed.2023.154756. Epub 2023 Mar 12.
Ref 2 IRP1 mediated ferroptosis reverses temozolomide resistance in glioblastoma via affecting LCN2/FPN1 signaling axis depended on NFKB2. iScience. 2023 Jul 12;26(8):107377. doi: 10.1016/j.isci.2023.107377. eCollection 2023 Aug 18.
Ref 3 A targetable LIFR-NF-B-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nat Commun. 2021 Dec 17;12(1):7333. doi: 10.1038/s41467-021-27452-9.
Ref 4 WTAP Mediates NUPR1 Regulation of LCN2 Through m(6)A Modification to Influence Ferroptosis, Thereby Promoting Breast Cancer Proliferation, Migration and Invasion. Biochem Genet. 2023 Jul 21. doi: 10.1007/s10528-023-10423-8. Online ahead of print.