Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10328)

Regulator Name	Hydroxycarboxylic acid receptor 1 (HCAR1)
Synonyms	GPR104, GPR81, HCA1; G-protein coupled receptor 104; G-protein coupled receptor 81 Click to Show/Hide
Gene Name	HCAR1
Gene ID	27198
Regulator Type	Protein coding
Uniprot ID	Q9BXC0
Sequence	MYNGSCCRIEGDTISQVMPPLLIVAFVLGALGNGVALCGFCFHMKTWKPSTVYLFNLAVA DFLLMICLPFRTDYYLRRRHWAFGDIPCRVGLFTLAMNRAGSIVFLTVVAADRYFKVVHP HHAVNTISTRVAAGIVCTLWALVILGTVYLLLENHLCVQETAVSCESFIMESANGWHDIM FQLEFFMPLGIILFCSFKIVWSLRRRQQLARQARMKKATRFIMVVAIVFITCYLPSVSAR LYFLWTVPSSACDPSVHGALHITLSFTYMNSMLDPLVYYFSSPSFPKFYNKLKICSLKPK QPGHSKTQRPEEMPISNLGRRSCISVANSFQSQSDGQWDPHIVEWH Click to Show/Hide
Family	G-protein coupled receptor 1 family
Function	Acts as a receptor for L-lactate and mediates its anti- lipolytic effect through a G(i)-protein-mediated pathway. Click to Show/Hide
HGNC ID	HGNC:4532
KEGG ID	hsa:27198

Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)

HCAR1 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

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Stearoyl-CoA desaturase (SCD) [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	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. Click to Show/Hide
Response regulation	Lactate regulates the ferroptosis of hepatocellular carcinoma cells. And blocking the lactate uptake via hydroxycarboxylic acid receptor 1 (HCAR1)/MCT1 inhibition promotes ferroptosis by activating the AMPK to downregulate SCD1, which may synergize with its acyl-coenzyme A synthetase 4 (ACSL4)-promoting effect to amplify the ferroptotic susceptibility.
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. 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.

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				[1]
Target for Ferroptosis	Driver
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 Process	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	Lactate regulates the ferroptosis of hepatocellular carcinoma cells. And blocking the lactate uptake via hydroxycarboxylic acid receptor 1 (HCAR1)/MCT1 inhibition promotes ferroptosis by activating the AMPK to downregulate SCD1, which may synergize with its acyl-coenzyme A synthetase 4 (ACSL4)-promoting effect to amplify the ferroptotic susceptibility.

Hepatocellular carcinoma [ICD-11: 2C12]

Disease Info

In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[1]
Target Regulator	Hydroxycarboxylic acid receptor 1 (HCAR1)		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 Process	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	Lactate regulates the ferroptosis of hepatocellular carcinoma cells. And blocking the lactate uptake via hydroxycarboxylic acid receptor 1 (HCAR1)/MCT1 inhibition promotes ferroptosis by activating the AMPK to downregulate SCD1, which may synergize with its acyl-coenzyme A synthetase 4 (ACSL4)-promoting effect to amplify the ferroptotic susceptibility.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[1]
Target Regulator	Hydroxycarboxylic acid receptor 1 (HCAR1)		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 Process	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	Lactate regulates the ferroptosis of hepatocellular carcinoma cells. And blocking the lactate uptake via hydroxycarboxylic acid receptor 1 (HCAR1)/MCT1 inhibition promotes ferroptosis by activating the AMPK to downregulate SCD1, which may synergize with its acyl-coenzyme A synthetase 4 (ACSL4)-promoting effect to amplify the ferroptotic susceptibility.

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	Hydroxycarboxylic acid receptor 1 (HCAR1)		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.

Lactate [Investigative]

Drug Info

In total 2 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 Process	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	Lactate regulates the ferroptosis of hepatocellular carcinoma cells. And blocking the lactate uptake via hydroxycarboxylic acid receptor 1 (HCAR1)/MCT1 inhibition promotes ferroptosis by activating the AMPK to downregulate SCD1, which may synergize with its acyl-coenzyme A synthetase 4 (ACSL4)-promoting effect to amplify the ferroptotic susceptibility.
Experiment 2 Reporting the Ferroptosis-centered Drug Response				[1]
Drug for Ferroptosis	Suppressor
Response Target	Long-chain-fatty-acid--CoA ligase 4 (ACSL4)		Driver	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 Process	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	Lactate regulates the ferroptosis of hepatocellular carcinoma cells. And blocking the lactate uptake via hydroxycarboxylic acid receptor 1 (HCAR1)/MCT1 inhibition promotes ferroptosis by activating the AMPK to downregulate SCD1, which may synergize with its acyl-coenzyme A synthetase 4 (ACSL4)-promoting effect to amplify the ferroptotic susceptibility.

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.

Ferroptosis Regulator Information

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Correspondence

Prof. Shuiping Liu