Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10144)
Regulator Name Sterol regulatory element-binding protein 1 (SREBF1)
Synonyms
Class D basic helix-loop-helix protein 1; Sterol regulatory element-binding transcription factor 1
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Gene Name SREBF1
Gene ID 6720
Regulator Type Protein coding
Uniprot ID P36956
Sequence
MDEPPFSEAALEQALGEPCDLDAALLTDIEDMLQLINNQDSDFPGLFDPPYAGSGAGGTD
PASPDTSSPGSLSPPPATLSSSLEAFLSGPQAAPSPLSPPQPAPTPLKMYPSMPAFSPGP
GIKEESVPLSILQTPTPQPLPGALLPQSFPAPAPPQFSSTPVLGYPSPPGGFSTGSPPGN
TQQPLPGLPLASPPGVPPVSLHTQVQSVVPQQLLTVTAAPTAAPVTTTVTSQIQQVPVLL
QPHFIKADSLLLTAMKTDGATVKAAGLSPLVSGTTVQTGPLPTLVSGGTILATVPLVVDA
EKLPINRLAAGSKAPASAQSRGEKRTAHNAIEKRYRSSINDKIIELKDLVVGTEAKLNKS
AVLRKAIDYIRFLQHSNQKLKQENLSLRTAVHKSKSLKDLVSACGSGGNTDVLMEGVKTE
VEDTLTPPPSDAGSPFQSSPLSLGSRGSGSGGSGSDSEPDSPVFEDSKAKPEQRPSLHSR
GMLDRSRLALCTLVFLCLSCNPLASLLGARGLPSPSDTTSVYHSPGRNVLGTESRDGPGW
AQWLLPPVVWLLNGLLVLVSLVLLFVYGEPVTRPHSGPAVYFWRHRKQADLDLARGDFAQ
AAQQLWLALRALGRPLPTSHLDLACSLLWNLIRHLLQRLWVGRWLAGRAGGLQQDCALRV
DASASARDAALVYHKLHQLHTMGKHTGGHLTATNLALSALNLAECAGDAVSVATLAEIYV
AAALRVKTSLPRALHFLTRFFLSSARQACLAQSGSVPPAMQWLCHPVGHRFFVDGDWSVL
STPWESLYSLAGNPVDPLAQVTQLFREHLLERALNCVTQPNPSPGSADGDKEFSDALGYL
QLLNSCSDAAGAPAYSFSISSSMATTTGVDPVAKWWASLTAVVIHWLRRDEEAAERLCPL
VEHLPRVLQESERPLPRAALHSFKAARALLGCAKAESGPASLTICEKASGYLQDSLATTP
ASSSIDKAVQLFLCDLLLVVRTSLWRQQQPPAPAPAAQGTSSRPQASALELRGFQRDLSS
LRRLAQSFRPAMRRVFLHEATARLMAGASPTRTHQLLDRSLRRRAGPGGKGGAVAELEPR
PTRREHAEALLLASCYLPPGFLSAPGQRVGMLAEAARTLEKLGDRRLLHDCQQMLMRLGG
GTTVTSS

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Family SREBP family
Function
Precursor of the transcription factor form (Processed sterol regulatory element- binding protein 1), which is embedded in the endoplasmic reticulum membrane. Low sterol concentrations promote processing of this form, releasing the transcription factor form that translocates into the nucleus and activates transcription of genes involved in cholesterol biosynthesis and lipid homeostasis.

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HGNC ID
HGNC:11289
KEGG ID hsa:6720
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
SREBF1 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
Stearoyl-CoA desaturase (SCD) [Suppressor]
 Target Info 
In total 4 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Drug Lactate Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 CAF cells Normal Carassius auratus CVCL_R883
HEK-293T cells Normal Homo sapiens CVCL_0063
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
In Vivo Model
Female mice aged around 6-7 weeks were used for this study, which were purchased through Laboratory Animal Center of Chongqing Medical University from Vital River Co. Ltd (Beijing, China).After one week, each mouse was injected subcutaneously with 100 uL of Huh-7 cell suspension (5 x 106 units) to establish the tumor model. The mice were grouped randomly, and then subjected to different treatments after subcutaneous tumors became visually detectable.

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Response regulation The monocarboxylate transporter 1 (MCT1)-mediated lactate uptake could promote ATP production in hepatocellular carcinoma (HCC) cells and deactivate the energy sensor AMP-activated protein kinase (AMPK), leading to the upregulation of SREBP1 (SREBF1) and the downstream stearoyl-coenzyme A (CoA) desaturase-1 (SCD1) to enhance the production of anti-ferroptosis monounsaturated fatty acids.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Suppressor
Responsed Disease Ovarian cancer ICD-11: 2C73
 Disease Info 
Responsed Drug NL01 Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 Anglne cells Ovarian carcinoma Homo sapiens CVCL_U287
HO8910PM cells Endocervical adenocarcinoma Homo sapiens CVCL_0310
In Vivo Model
BALB/c Nude female mice were adjusted for 7 days in a SPF room and divided into 2 groups (6 mice per group): DMSO and NL01 (5 mg/kg). NL01 was dissolved in 1% carboxymethylcellulose (Millipore, USA). DMSO (control) used the same volume of vehicle (1% carboxymethylcellulose). HO8910PM cells were grown in tissue culture, and counted. 1 x 106 cells were inoculated to subcutaneously. Ten days after inoculation, the drugs were administered every five days subcutaneously to the mice for 15 days.

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Response regulation NL01 induced iron death and inhibited ovarian cancer proliferation. NL01 was able to reduce the expression of HCAR1/MCT1 and activate the AMPK signaling pathway, which in turn induced cellular ferroptosis via SREBP1 (SREBF1) pathway. SCD1 (Stearoyl-CoA desaturase-1) is the downstream target of SREBP1. Further study showed that NL01 promoted the downregulation of GPX4 expression.
Experiment 3 Reporting the Ferroptosis Target of This Regulator [3]
Target for Ferroptosis Suppressor
Responsed Disease Nonalcoholic fatty liver disease ICD-11: DB92
 Disease Info 
Responsed Drug D-(-)-Fructose Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model
 hLCs (Liver cells)
In Vivo Model
Four-week-old male and female C57BL/6N mice were obtained from the Central Lab Animal Inc. (Seoul, South Korea) and housed in 42 x 27 x 15 cm polycarbonate cages (six mice per cage). The animals were assigned into either the control group (n = 12; six mice per sex) or fructose intervention group (n = 12; six mice per sex). After a week of acclimation, the fructose group was subjected to 34% fructose in deionized water (wt:vol) over six weeks to induce NAFLD conditions as previously described.11 To note, compared to conventional sugary beverages (e.g., soft drinks), the supplementation level of fructose is higher (11% vs. 34%) to induce liver damage markers within a reasonable intervention time range (i.e., 6 weeks).

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Response regulation The protein expressions of SREBP1 and its downstream targets ACC1, FASN and SCD1 were all increased in fructose-treated AML12 hepatocytes, which demonstrates fructose mediated upregulation of SREBP1. MiR-33-5p (miR-33) was identified as the key miRNA responsible for SREBP1 regulation upon fructose intake, which was validated by in vitro transfection assay. Collectively, fructose-induced oxidative damage induces ferroptosis, and miR-33 could be used as a serological biomarker of fructose-induced non-alcoholic fatty liver disease (NAFLD).
Experiment 4 Reporting the Ferroptosis Target of This Regulator [5]
Target for Ferroptosis Suppressor
Responsed Disease Fibrosarcoma ICD-11: 2B53
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
PI3K-Akt signaling pathway hsa04151
Cell Process Cell ferroptosis
In Vitro Model
 HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
MDA-MB-453 cells Breast adenocarcinoma Homo sapiens CVCL_0418
BT-474 cells Invasive breast carcinoma Homo sapiens CVCL_0179
MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
T-47D cells Invasive breast carcinoma Homo sapiens CVCL_0553
U-87MG cells Glioblastoma Homo sapiens CVCL_GP63
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
PC-3 cells Prostate carcinoma Homo sapiens CVCL_0035
DU145 cells Prostate carcinoma Homo sapiens CVCL_0105
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
LN-229 cells Glioblastoma Homo sapiens CVCL_0393
SK-MEL-2 cells (MEK inhibitor-resistant) cells Melanoma Homo sapiens CVCL_0069
In Vivo Model
For the in vivo xenograft mouse model, 17-b-estradiol 60-d release pellets (Innovative Research of America) were implanted subcutaneously into the left flank 7 d before tumor inoculation. GPX4 iKO BT474 cells were inoculated by injecting 5 x 106 cells in 50% Matrigel subcutaneously in the right flank of 6- to 8-wk-old female athymicnu/numice (Envigo). For PC-3 tumor models, male athymic nu/nu mice aged 5 to 6 wk were injected in the right flank with 5 x 106 PC-3 cells.

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Response regulation Hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise of preclinical models in Fibrosarcoma.
Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [4]
Target for Ferroptosis Suppressor
Responsed Disease Gastric cancer ICD-11: 2B72
 Disease Info 
Responsed Drug Apatinib Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model
 MGC-803 cells Gastric mucinous adenocarcinoma Homo sapiens CVCL_5334
MKN45 cells Gastric adenocarcinoma Homo sapiens CVCL_0434
BGC-823 cells Gastric carcinoma Homo sapiens CVCL_3360
SGC-7901 cells Gastric carcinoma Homo sapiens CVCL_0520
AGS cells Gastric adenocarcinoma Homo sapiens CVCL_0139
In Vivo Model
Female nude mice (BALB/c, nu/nu, 18-22 g, 4-5 weeks old) were obtained from Guangdong Medical Laboratory Animal center, China, and maintained under specific pathogen-free conditions on a 12h/12h light/dark cycle. Each mouse was injected subcutaneously with eight million luciferase-expressing cells resuspended in 50 ul of PBS and 50 ul of Matrigel (BD Biosciences). When a palpable mass had developed, the mice were randomly divided into five groups: apatinib (50 mg/kg/day oral dose for 14 days); RSL3 (100 mg/kg injection of RSL3 twice per week for 2 weeks at the same site); both; apatinib (50 mg/kg/day oral dose for 14 days) plus vitamin E (100 mg/kg/day oral dose for 14 days); and vehicle (DMSO, 100 ul oral dose for 14 days).

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Response regulation Apatinib exerted antitumor effects against gastric cancer cells in vitro and in vivo through the induction of lipid peroxidation mediated by GPX4, then lead to ferroptosis. Furethermore, we found apatinib inhibited transcription of GPX4 via a SREBP1a-mediated pathway. These results indicated that GPX4 may be a potential target for anti-GC efficacy evaluation and treatment of apatinib.
Gastric cancer [ICD-11: 2B72]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [4]
Target Regulator Sterol regulatory element-binding protein 1 (SREBF1) Protein coding
 Regulator Info 
Responsed Drug Apatinib Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model
 MGC-803 cells Gastric mucinous adenocarcinoma Homo sapiens CVCL_5334
MKN45 cells Gastric adenocarcinoma Homo sapiens CVCL_0434
BGC-823 cells Gastric carcinoma Homo sapiens CVCL_3360
SGC-7901 cells Gastric carcinoma Homo sapiens CVCL_0520
AGS cells Gastric adenocarcinoma Homo sapiens CVCL_0139
In Vivo Model
Female nude mice (BALB/c, nu/nu, 18-22 g, 4-5 weeks old) were obtained from Guangdong Medical Laboratory Animal center, China, and maintained under specific pathogen-free conditions on a 12h/12h light/dark cycle. Each mouse was injected subcutaneously with eight million luciferase-expressing cells resuspended in 50 ul of PBS and 50 ul of Matrigel (BD Biosciences). When a palpable mass had developed, the mice were randomly divided into five groups: apatinib (50 mg/kg/day oral dose for 14 days); RSL3 (100 mg/kg injection of RSL3 twice per week for 2 weeks at the same site); both; apatinib (50 mg/kg/day oral dose for 14 days) plus vitamin E (100 mg/kg/day oral dose for 14 days); and vehicle (DMSO, 100 ul oral dose for 14 days).

    Click to Show/Hide
Response regulation Apatinib exerted antitumor effects against gastric cancer cells in vitro and in vivo through the induction of lipid peroxidation mediated by GPX4, then lead to ferroptosis. Furethermore, we found apatinib inhibited transcription of GPX4 via a SREBP1a-mediated pathway. These results indicated that GPX4 may be a potential target for anti-GC efficacy evaluation and treatment of apatinib.
Hepatocellular carcinoma [ICD-11: 2C12]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Sterol regulatory element-binding protein 1 (SREBF1) Protein coding
 Regulator Info 
Responsed Drug Lactate Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 CAF cells Normal Carassius auratus CVCL_R883
HEK-293T cells Normal Homo sapiens CVCL_0063
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
In Vivo Model
Female mice aged around 6-7 weeks were used for this study, which were purchased through Laboratory Animal Center of Chongqing Medical University from Vital River Co. Ltd (Beijing, China).After one week, each mouse was injected subcutaneously with 100 uL of Huh-7 cell suspension (5 x 106 units) to establish the tumor model. The mice were grouped randomly, and then subjected to different treatments after subcutaneous tumors became visually detectable.

    Click to Show/Hide
Response regulation The monocarboxylate transporter 1 (MCT1)-mediated lactate uptake could promote ATP production in hepatocellular carcinoma (HCC) cells and deactivate the energy sensor AMP-activated protein kinase (AMPK), leading to the upregulation of SREBP1 (SREBF1) and the downstream stearoyl-coenzyme A (CoA) desaturase-1 (SCD1) to enhance the production of anti-ferroptosis monounsaturated fatty acids.
Ovarian cancer [ICD-11: 2C73]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Sterol regulatory element-binding protein 1 (SREBF1) Protein coding
 Regulator Info 
Responsed Drug NL01 Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 Anglne cells Ovarian carcinoma Homo sapiens CVCL_U287
HO8910PM cells Endocervical adenocarcinoma Homo sapiens CVCL_0310
In Vivo Model
BALB/c Nude female mice were adjusted for 7 days in a SPF room and divided into 2 groups (6 mice per group): DMSO and NL01 (5 mg/kg). NL01 was dissolved in 1% carboxymethylcellulose (Millipore, USA). DMSO (control) used the same volume of vehicle (1% carboxymethylcellulose). HO8910PM cells were grown in tissue culture, and counted. 1 x 106 cells were inoculated to subcutaneously. Ten days after inoculation, the drugs were administered every five days subcutaneously to the mice for 15 days.

    Click to Show/Hide
Response regulation NL01 induced iron death and inhibited ovarian cancer proliferation. NL01 was able to reduce the expression of HCAR1/MCT1 and activate the AMPK signaling pathway, which in turn induced cellular ferroptosis via SREBP1 (SREBF1) pathway. SCD1 (Stearoyl-CoA desaturase-1) is the downstream target of SREBP1. Further study showed that NL01 promoted the downregulation of GPX4 expression.
Nonalcoholic fatty liver disease [ICD-11: DB92]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator Sterol regulatory element-binding protein 1 (SREBF1) Protein coding
 Regulator Info 
Responsed Drug D-(-)-Fructose Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model
 hLCs (Liver cells)
In Vivo Model
Four-week-old male and female C57BL/6N mice were obtained from the Central Lab Animal Inc. (Seoul, South Korea) and housed in 42 x 27 x 15 cm polycarbonate cages (six mice per cage). The animals were assigned into either the control group (n = 12; six mice per sex) or fructose intervention group (n = 12; six mice per sex). After a week of acclimation, the fructose group was subjected to 34% fructose in deionized water (wt:vol) over six weeks to induce NAFLD conditions as previously described.11 To note, compared to conventional sugary beverages (e.g., soft drinks), the supplementation level of fructose is higher (11% vs. 34%) to induce liver damage markers within a reasonable intervention time range (i.e., 6 weeks).

    Click to Show/Hide
Response regulation The protein expressions of SREBP1 and its downstream targets ACC1, FASN and SCD1 were all increased in fructose-treated AML12 hepatocytes, which demonstrates fructose mediated upregulation of SREBP1. MiR-33-5p (miR-33) was identified as the key miRNA responsible for SREBP1 regulation upon fructose intake, which was validated by in vitro transfection assay. Collectively, fructose-induced oxidative damage induces ferroptosis, and miR-33 could be used as a serological biomarker of fructose-induced non-alcoholic fatty liver disease (NAFLD).
Fibrosarcoma [ICD-11: 2B53]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [5]
Target Regulator Sterol regulatory element-binding protein 1 (SREBF1) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
PI3K-Akt signaling pathway hsa04151
Cell Process Cell ferroptosis
In Vitro Model
 HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
MDA-MB-453 cells Breast adenocarcinoma Homo sapiens CVCL_0418
BT-474 cells Invasive breast carcinoma Homo sapiens CVCL_0179
MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
T-47D cells Invasive breast carcinoma Homo sapiens CVCL_0553
U-87MG cells Glioblastoma Homo sapiens CVCL_GP63
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
PC-3 cells Prostate carcinoma Homo sapiens CVCL_0035
DU145 cells Prostate carcinoma Homo sapiens CVCL_0105
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
LN-229 cells Glioblastoma Homo sapiens CVCL_0393
SK-MEL-2 cells (MEK inhibitor-resistant) cells Melanoma Homo sapiens CVCL_0069
In Vivo Model
For the in vivo xenograft mouse model, 17-b-estradiol 60-d release pellets (Innovative Research of America) were implanted subcutaneously into the left flank 7 d before tumor inoculation. GPX4 iKO BT474 cells were inoculated by injecting 5 x 106 cells in 50% Matrigel subcutaneously in the right flank of 6- to 8-wk-old female athymicnu/numice (Envigo). For PC-3 tumor models, male athymic nu/nu mice aged 5 to 6 wk were injected in the right flank with 5 x 106 PC-3 cells.

    Click to Show/Hide
Response regulation Hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise of preclinical models in Fibrosarcoma.
Apatinib [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [4]
Drug for Ferroptosis Inducer
Response Target Phospholipid hydroperoxide glutathione peroxidase (GPX4) Suppressor
 Target Info 
Responsed Disease Gastric cancer ICD-11: 2B72
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model
 MGC-803 cells Gastric mucinous adenocarcinoma Homo sapiens CVCL_5334
MKN45 cells Gastric adenocarcinoma Homo sapiens CVCL_0434
BGC-823 cells Gastric carcinoma Homo sapiens CVCL_3360
SGC-7901 cells Gastric carcinoma Homo sapiens CVCL_0520
AGS cells Gastric adenocarcinoma Homo sapiens CVCL_0139
In Vivo Model
Female nude mice (BALB/c, nu/nu, 18-22 g, 4-5 weeks old) were obtained from Guangdong Medical Laboratory Animal center, China, and maintained under specific pathogen-free conditions on a 12h/12h light/dark cycle. Each mouse was injected subcutaneously with eight million luciferase-expressing cells resuspended in 50 ul of PBS and 50 ul of Matrigel (BD Biosciences). When a palpable mass had developed, the mice were randomly divided into five groups: apatinib (50 mg/kg/day oral dose for 14 days); RSL3 (100 mg/kg injection of RSL3 twice per week for 2 weeks at the same site); both; apatinib (50 mg/kg/day oral dose for 14 days) plus vitamin E (100 mg/kg/day oral dose for 14 days); and vehicle (DMSO, 100 ul oral dose for 14 days).

    Click to Show/Hide
Response regulation Apatinib exerted antitumor effects against gastric cancer cells in vitro and in vivo through the induction of lipid peroxidation mediated by GPX4, then lead to ferroptosis. Furethermore, we found apatinib inhibited transcription of GPX4 via a SREBP1a-mediated pathway. These results indicated that GPX4 may be a potential target for anti-GC efficacy evaluation and treatment of apatinib.
D-(-)-Fructose [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [3]
Drug for Ferroptosis Inducer
Response Target Stearoyl-CoA desaturase (SCD) Suppressor
 Target Info 
Responsed Disease Nonalcoholic fatty liver disease ICD-11: DB92
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model
 hLCs (Liver cells)
In Vivo Model
Four-week-old male and female C57BL/6N mice were obtained from the Central Lab Animal Inc. (Seoul, South Korea) and housed in 42 x 27 x 15 cm polycarbonate cages (six mice per cage). The animals were assigned into either the control group (n = 12; six mice per sex) or fructose intervention group (n = 12; six mice per sex). After a week of acclimation, the fructose group was subjected to 34% fructose in deionized water (wt:vol) over six weeks to induce NAFLD conditions as previously described.11 To note, compared to conventional sugary beverages (e.g., soft drinks), the supplementation level of fructose is higher (11% vs. 34%) to induce liver damage markers within a reasonable intervention time range (i.e., 6 weeks).

    Click to Show/Hide
Response regulation The protein expressions of SREBP1 and its downstream targets ACC1, FASN and SCD1 were all increased in fructose-treated AML12 hepatocytes, which demonstrates fructose mediated upregulation of SREBP1. MiR-33-5p (miR-33) was identified as the key miRNA responsible for SREBP1 regulation upon fructose intake, which was validated by in vitro transfection assay. Collectively, fructose-induced oxidative damage induces ferroptosis, and miR-33 could be used as a serological biomarker of fructose-induced non-alcoholic fatty liver disease (NAFLD).
Lactate [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 Stearoyl-CoA desaturase (SCD) Suppressor
 Target Info 
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 CAF cells Normal Carassius auratus CVCL_R883
HEK-293T cells Normal Homo sapiens CVCL_0063
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
In Vivo Model
Female mice aged around 6-7 weeks were used for this study, which were purchased through Laboratory Animal Center of Chongqing Medical University from Vital River Co. Ltd (Beijing, China).After one week, each mouse was injected subcutaneously with 100 uL of Huh-7 cell suspension (5 x 106 units) to establish the tumor model. The mice were grouped randomly, and then subjected to different treatments after subcutaneous tumors became visually detectable.

    Click to Show/Hide
Response regulation The monocarboxylate transporter 1 (MCT1)-mediated lactate uptake could promote ATP production in hepatocellular carcinoma (HCC) cells and deactivate the energy sensor AMP-activated protein kinase (AMPK), leading to the upregulation of SREBP1 (SREBF1) and the downstream stearoyl-coenzyme A (CoA) desaturase-1 (SCD1) to enhance the production of anti-ferroptosis monounsaturated fatty acids.
NL01 [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [2]
Drug for Ferroptosis Inducer
Response Target Stearoyl-CoA desaturase (SCD) Suppressor
 Target Info 
Responsed Disease Ovarian cancer ICD-11: 2C73
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
AMPK signaling pathway hsa04152
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 Anglne cells Ovarian carcinoma Homo sapiens CVCL_U287
HO8910PM cells Endocervical adenocarcinoma Homo sapiens CVCL_0310
In Vivo Model
BALB/c Nude female mice were adjusted for 7 days in a SPF room and divided into 2 groups (6 mice per group): DMSO and NL01 (5 mg/kg). NL01 was dissolved in 1% carboxymethylcellulose (Millipore, USA). DMSO (control) used the same volume of vehicle (1% carboxymethylcellulose). HO8910PM cells were grown in tissue culture, and counted. 1 x 106 cells were inoculated to subcutaneously. Ten days after inoculation, the drugs were administered every five days subcutaneously to the mice for 15 days.

    Click to Show/Hide
Response regulation NL01 induced iron death and inhibited ovarian cancer proliferation. NL01 was able to reduce the expression of HCAR1/MCT1 and activate the AMPK signaling pathway, which in turn induced cellular ferroptosis via SREBP1 (SREBF1) pathway. SCD1 (Stearoyl-CoA desaturase-1) is the downstream target of SREBP1. Further study showed that NL01 promoted the downregulation of GPX4 expression.
References
Ref 1 HCAR1/MCT1 Regulates Tumor Ferroptosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeutic Implications. Cell Rep. 2020 Dec 8;33(10):108487. doi: 10.1016/j.celrep.2020.108487.
Ref 2 Curcumin derivative NL01 induces ferroptosis in ovarian cancer cells via HCAR1/MCT1 signaling. Cell Signal. 2023 Sep;109:110791. doi: 10.1016/j.cellsig.2023.110791. Epub 2023 Jul 3.
Ref 3 The role of microRNA-33 as a key regulator in hepatic lipogenesis signaling and a potential serological biomarker for NAFLD with excessive dietary fructose consumption in C57BL/6N mice. Food Funct. 2021 Jan 21;12(2):656-667. doi: 10.1039/d0fo02286a. Epub 2021 Jan 6.
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