Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10198)

Regulator Name	Transcription factor p65 (RELA)
Synonyms	NFKB3; Nuclear factor NF-kappa-B p65 subunit; Nuclear factor of kappa light polypeptide gene enhancer in B-cells 3 Click to Show/Hide
Gene Name	RELA
Gene ID	5970
Regulator Type	Protein coding
Uniprot ID	Q04206
Sequence	MDELFPLIFPAEPAQASGPYVEIIEQPKQRGMRFRYKCEGRSAGSIPGERSTDTTKTHPT IKINGYTGPGTVRISLVTKDPPHRPHPHELVGKDCRDGFYEAELCPDRCIHSFQNLGIQC VKKRDLEQAISQRIQTNNNPFQVPIEEQRGDYDLNAVRLCFQVTVRDPSGRPLRLPPVLS HPIFDNRAPNTAELKICRVNRNSGSCLGGDEIFLLCDKVQKEDIEVYFTGPGWEARGSFS QADVHRQVAIVFRTPPYADPSLQAPVRVSMQLRRPSDRELSEPMEFQYLPDTDDRHRIEE KRKRTYETFKSIMKKSPFSGPTDPRPPPRRIAVPSRSSASVPKPAPQPYPFTSSLSTINY DEFPTMVFPSGQISQASALAPAPPQVLPQAPAPAPAPAMVSALAQAPAPVPVLAPGPPQA VAPPAPKPTQAGEGTLSEALLQLQFDDEDLGALLGNSTDPAVFTDLASVDNSEFQQLLNQ GIPVAPHTTEPMLMEYPEAITRLVTGAQRPPDPAPAPLGAPGLPNGLLSGDEDFSSIADM DFSALLSQISS Click to Show/Hide
Function	NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain- containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The heterodimeric RELA-NFKB1 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. The NF-kappa-B heterodimeric RELA-NFKB1 and RELA-REL complexes, for instance, function as transcriptional activators. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I- kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The inhibitory effect of I- kappa-B on NF-kappa-B through retention in the cytoplasm is exerted primarily through the interaction with RELA. RELA shows a weak DNA- binding site which could contribute directly to DNA binding in the NF- kappa-B complex. Beside its activity as a direct transcriptional activator, it is also able to modulate promoters accessibility to transcription factors and thereby indirectly regulate gene expression. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T- cells. The NF-kappa-B homodimeric RELA-RELA complex appears to be involved in invasin-mediated activation of IL-8 expression. Key transcription factor regulating the IFN response during SARS-CoV-2 infection. Click to Show/Hide
HGNC ID	HGNC:9955
KEGG ID	hsa:5970

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

RELA 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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Unspecific Target [Unspecific Target]

In total 4 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[1]
Responsed Disease	Nasopharyngeal cancer		ICD-11: 2B6B	Disease Info
Responsed Drug	Lupeol		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	NF-kappa B signaling pathway			hsa04064
	Apoptosis			hsa04210
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vivo Model	BALB/c nude mice (6-week-old) were purchased from Junke biology Co., Ltd (Nanjing, China). All mice were individually housed and had free access to food and water. Then, 58?F and CNE1 cells (5x10⁶ cells in 200 l medium) were inoculated into right flank of mice. Mice were divided into 2 groups: sham group and 10 mg/kg lupeol group (5 mice per group). Specifically, mice of the 10 mg/kg lupeol group were intraperitoneally administrated with lupeol (10 mg/kg, every 3 days) referring to previous studies [Citation23,Citation24]. Mice in the sham group received an equivalent volume of PBS. At day 40 after lupeol treatment, mice were euthanized by cervical dislocation after anesthetizing with 3% isoflurane. The tumor volume and weight were recorded, respectively. Animal experiments were conducted following the approval of the Ethics Committee of Shenzhen Peoples Hospital (No. SYXK(YUE)2017-0174). Click to Show/Hide
Response regulation	Lupeol significantly elevated AMPK phosphorylation, and reduced the levels of p-IB and nuclear NF-kB p65 (RELA). Lupeol exerted the anti-cancer impacts by inducing oxidative stress, ferroptosis and apoptosis, and suppressing inflammation via the AMPK/NF-kB pathway in nasopharyngeal carcinoma.
Experiment 2 Reporting the Ferroptosis Target of This Regulator				[2]
Responsed Disease	Breast cancer		ICD-11: 2C60	Disease Info
Responsed Drug	Isoliquiritin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Apoptosis			hsa04210
	Gluconeogenesis			hsa00010
	NF-kappa B signaling pathway			hsa04064
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	MDA-MB-231 cells	Breast adenocarcinoma	Homo sapiens	CVCL_0062
	MCF-7 cells	Breast carcinoma	Homo sapiens	CVCL_0031
In Vivo Model	BALB/c nude mice (4 weeks old) were obtained from Charles river (Beijing, China). Mice were fed in a temperature-controlled SPF animal room with a 12-h cycle of light-dark. All animal experiments were ratified by the Animal Research Ethics Committee of Shenzhen Bao'an Traditional Chinese Medicine Hospital Group. 10 mice were subcutaneously inoculated with a total of 210⁶ of MDA-MB-231 cells and then divided into two groups at random, including the Model group and Iso group. Mice in the Iso group were intraperitoneally injected with 25?mg/kg/d Iso, while mice in the Model group were supplied with the same amount of phosphate buffer saline (PBS, Beyotime). Tumor volume was monitored every 4 d. Mice were sacrificed with the intraperitoneal introduction of sodium pentobarbital (100 mg/kg) after tumor cells treatment for 31 d, and the tumor samples were removed and weighed. Tumor volume was determined according to the formula: volume = 1/2 x length x width². Click to Show/Hide
Response regulation	Isoliquiritin notably counteracted the LPS-induced relative protein levels of p-p50/p50, p-p65/p65 (RELA), and IB, and the levels of ferroptosis, oxidative stress, glycolysis, and inflammation. Iso inhibited the NF-kB signaling to regulate ferroptosis and improved Dox-resistance in breast cancer.
Experiment 3 Reporting the Ferroptosis Target of This Regulator				[3]
Responsed Disease	Intervertebral disc degeneration		ICD-11: FA80	Disease Info
Responsed Drug	Hesperidin		Approved	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	NF-kappa B signaling pathway			hsa04064
Cell Process	Cell ferroptosis
In Vitro Model	hNPCs (Human nucleus pulposus cells)
In Vivo Model	Male C57BL/6 mice (10-12 weeks) were devoted to generate needle puncture-induced intervertebral disc degeneration model. For intervertebral disc degeneration (IVDD) treatment, hesperidin was administratedorally and the dose was calculated in reference to previous studies using themetrological conversion formula between human and mouse. The dosein mice is = 5.5 mg/kg x 70 kg x 0.0026/20g = 9.1 x 5.5 mg/kg = 50.05 mg/kg ~50 mg/kg. Click to Show/Hide
Response regulation	The current study proved for the first time that Hesperidin may protect HNP cells from degeneration by suppressing ferroptosis in an oxidative stress-dependent via enhancing the expression of Nrf2 and suppressing the NF-kB pathway. The evidence will provide a possible basis for future targeted treatment for intervertebral disc degeneration.
Experiment 4 Reporting the Ferroptosis Target of This Regulator				[4]
Responsed Disease	Ulcerative colitis		ICD-11: DD71	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	NF-kappa B signaling pathway			hsa04064
Cell Process	Cell ferroptosis
In Vitro Model	HCoEpiC (Human normal colonic epithelial cells)
In Vivo Model	All mice involved had a C57BL/6 gene background. All mice with age- and sex-matched between 6 and 8 weeks of age were assigned randomly to groups. To induce experimental colitis, the mice were challenged with 3% dextran sulfate sodium (DSS; MP Biomedicals, LLC, Solon, OH) in drinking water for 7 days. The control mice were allowed to drink water only at the same time. To administer ferrostatin-1 (Fer1) in vivo, we intraperitoneal injected mice daily with Fer1 (Merck, Darmstadt, Germany, 2.5 umol/kg body weight), and the corresponding control mice were injected intraperitoneally with normal saline. Click to Show/Hide
Response regulation	Ferroptosis contributes to ulcerative colitis (UC) via ER stress-mediated IEC cell death, and that NF-B p65 (RELA) phosphorylation suppresses ER stress-mediated IEC ferroptosis to alleviate UC.

Nasopharyngeal cancer [ICD-11: 2B6B]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[1]
Target Regulator	Transcription factor p65 (RELA)	Protein coding	Regulator Info
Responsed Drug	Lupeol	Investigative	Drug Info
Pathway Response	Fatty acid metabolism		hsa01212
	Ferroptosis		hsa04216
	NF-kappa B signaling pathway		hsa04064
	Apoptosis		hsa04210
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vivo Model	BALB/c nude mice (6-week-old) were purchased from Junke biology Co., Ltd (Nanjing, China). All mice were individually housed and had free access to food and water. Then, 58?F and CNE1 cells (5x10⁶ cells in 200 l medium) were inoculated into right flank of mice. Mice were divided into 2 groups: sham group and 10 mg/kg lupeol group (5 mice per group). Specifically, mice of the 10 mg/kg lupeol group were intraperitoneally administrated with lupeol (10 mg/kg, every 3 days) referring to previous studies [Citation23,Citation24]. Mice in the sham group received an equivalent volume of PBS. At day 40 after lupeol treatment, mice were euthanized by cervical dislocation after anesthetizing with 3% isoflurane. The tumor volume and weight were recorded, respectively. Animal experiments were conducted following the approval of the Ethics Committee of Shenzhen Peoples Hospital (No. SYXK(YUE)2017-0174). Click to Show/Hide
Response regulation	Lupeol significantly elevated AMPK phosphorylation, and reduced the levels of p-IB and nuclear NF-kB p65 (RELA). Lupeol exerted the anti-cancer impacts by inducing oxidative stress, ferroptosis and apoptosis, and suppressing inflammation via the AMPK/NF-kB pathway in nasopharyngeal carcinoma.

Breast cancer [ICD-11: 2C60]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[2]
Target Regulator	Transcription factor p65 (RELA)		Protein coding	Regulator Info
Responsed Drug	Isoliquiritin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Apoptosis			hsa04210
	Gluconeogenesis			hsa00010
	NF-kappa B signaling pathway			hsa04064
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	MDA-MB-231 cells	Breast adenocarcinoma	Homo sapiens	CVCL_0062
	MCF-7 cells	Breast carcinoma	Homo sapiens	CVCL_0031
In Vivo Model	BALB/c nude mice (4 weeks old) were obtained from Charles river (Beijing, China). Mice were fed in a temperature-controlled SPF animal room with a 12-h cycle of light-dark. All animal experiments were ratified by the Animal Research Ethics Committee of Shenzhen Bao'an Traditional Chinese Medicine Hospital Group. 10 mice were subcutaneously inoculated with a total of 210⁶ of MDA-MB-231 cells and then divided into two groups at random, including the Model group and Iso group. Mice in the Iso group were intraperitoneally injected with 25?mg/kg/d Iso, while mice in the Model group were supplied with the same amount of phosphate buffer saline (PBS, Beyotime). Tumor volume was monitored every 4 d. Mice were sacrificed with the intraperitoneal introduction of sodium pentobarbital (100 mg/kg) after tumor cells treatment for 31 d, and the tumor samples were removed and weighed. Tumor volume was determined according to the formula: volume = 1/2 x length x width². Click to Show/Hide
Response regulation	Isoliquiritin notably counteracted the LPS-induced relative protein levels of p-p50/p50, p-p65/p65 (RELA), and IB, and the levels of ferroptosis, oxidative stress, glycolysis, and inflammation. Iso inhibited the NF-kB signaling to regulate ferroptosis and improved Dox-resistance in breast cancer.

Intervertebral disc degeneration [ICD-11: FA80]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[3]
Target Regulator	Transcription factor p65 (RELA)	Protein coding	Regulator Info
Responsed Drug	Hesperidin	Approved	Drug Info
Pathway Response	Fatty acid metabolism		hsa01212
	NF-kappa B signaling pathway		hsa04064
Cell Process	Cell ferroptosis
In Vitro Model	hNPCs (Human nucleus pulposus cells)
In Vivo Model	Male C57BL/6 mice (10-12 weeks) were devoted to generate needle puncture-induced intervertebral disc degeneration model. For intervertebral disc degeneration (IVDD) treatment, hesperidin was administratedorally and the dose was calculated in reference to previous studies using themetrological conversion formula between human and mouse. The dosein mice is = 5.5 mg/kg x 70 kg x 0.0026/20g = 9.1 x 5.5 mg/kg = 50.05 mg/kg ~50 mg/kg. Click to Show/Hide
Response regulation	The current study proved for the first time that Hesperidin may protect HNP cells from degeneration by suppressing ferroptosis in an oxidative stress-dependent via enhancing the expression of Nrf2 and suppressing the NF-kB pathway. The evidence will provide a possible basis for future targeted treatment for intervertebral disc degeneration.

Ulcerative colitis [ICD-11: DD71]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response			[4]
Target Regulator	Transcription factor p65 (RELA)	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	HCoEpiC (Human normal colonic epithelial cells)
In Vivo Model	All mice involved had a C57BL/6 gene background. All mice with age- and sex-matched between 6 and 8 weeks of age were assigned randomly to groups. To induce experimental colitis, the mice were challenged with 3% dextran sulfate sodium (DSS; MP Biomedicals, LLC, Solon, OH) in drinking water for 7 days. The control mice were allowed to drink water only at the same time. To administer ferrostatin-1 (Fer1) in vivo, we intraperitoneal injected mice daily with Fer1 (Merck, Darmstadt, Germany, 2.5 umol/kg body weight), and the corresponding control mice were injected intraperitoneally with normal saline. Click to Show/Hide
Response regulation	Ferroptosis contributes to ulcerative colitis (UC) via ER stress-mediated IEC cell death, and that NF-B p65 (RELA) phosphorylation suppresses ER stress-mediated IEC ferroptosis to alleviate UC.

Hesperidin [Approved]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response			[3]
Drug for Ferroptosis	Suppressor
Response Target	Unspecific Target
Responsed Disease	Intervertebral disc degeneration	ICD-11: FA80	Disease Info
Pathway Response	Fatty acid metabolism		hsa01212
	NF-kappa B signaling pathway		hsa04064
Cell Process	Cell ferroptosis
In Vitro Model	hNPCs (Human nucleus pulposus cells)
In Vivo Model	Male C57BL/6 mice (10-12 weeks) were devoted to generate needle puncture-induced intervertebral disc degeneration model. For intervertebral disc degeneration (IVDD) treatment, hesperidin was administratedorally and the dose was calculated in reference to previous studies using themetrological conversion formula between human and mouse. The dosein mice is = 5.5 mg/kg x 70 kg x 0.0026/20g = 9.1 x 5.5 mg/kg = 50.05 mg/kg ~50 mg/kg. Click to Show/Hide
Response regulation	The current study proved for the first time that Hesperidin may protect HNP cells from degeneration by suppressing ferroptosis in an oxidative stress-dependent via enhancing the expression of Nrf2 and suppressing the NF-kB pathway. The evidence will provide a possible basis for future targeted treatment for intervertebral disc degeneration.

Lupeol [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response			[1]
Drug for Ferroptosis	Inducer
Response Target	Unspecific Target
Responsed Disease	Nasopharyngeal cancer	ICD-11: 2B6B	Disease Info
Pathway Response	Fatty acid metabolism		hsa01212
	Ferroptosis		hsa04216
	NF-kappa B signaling pathway		hsa04064
	Apoptosis		hsa04210
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vivo Model	BALB/c nude mice (6-week-old) were purchased from Junke biology Co., Ltd (Nanjing, China). All mice were individually housed and had free access to food and water. Then, 58?F and CNE1 cells (5x10⁶ cells in 200 l medium) were inoculated into right flank of mice. Mice were divided into 2 groups: sham group and 10 mg/kg lupeol group (5 mice per group). Specifically, mice of the 10 mg/kg lupeol group were intraperitoneally administrated with lupeol (10 mg/kg, every 3 days) referring to previous studies [Citation23,Citation24]. Mice in the sham group received an equivalent volume of PBS. At day 40 after lupeol treatment, mice were euthanized by cervical dislocation after anesthetizing with 3% isoflurane. The tumor volume and weight were recorded, respectively. Animal experiments were conducted following the approval of the Ethics Committee of Shenzhen Peoples Hospital (No. SYXK(YUE)2017-0174). Click to Show/Hide
Response regulation	Lupeol significantly elevated AMPK phosphorylation, and reduced the levels of p-IB and nuclear NF-kB p65 (RELA). Lupeol exerted the anti-cancer impacts by inducing oxidative stress, ferroptosis and apoptosis, and suppressing inflammation via the AMPK/NF-kB pathway in nasopharyngeal carcinoma.

Isoliquiritin [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	Unspecific Target
Responsed Disease	Breast cancer		ICD-11: 2C60	Disease Info
Pathway Response	Ferroptosis			hsa04216
	Apoptosis			hsa04210
	Gluconeogenesis			hsa00010
	NF-kappa B signaling pathway			hsa04064
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	MDA-MB-231 cells	Breast adenocarcinoma	Homo sapiens	CVCL_0062
	MCF-7 cells	Breast carcinoma	Homo sapiens	CVCL_0031
In Vivo Model	BALB/c nude mice (4 weeks old) were obtained from Charles river (Beijing, China). Mice were fed in a temperature-controlled SPF animal room with a 12-h cycle of light-dark. All animal experiments were ratified by the Animal Research Ethics Committee of Shenzhen Bao'an Traditional Chinese Medicine Hospital Group. 10 mice were subcutaneously inoculated with a total of 210⁶ of MDA-MB-231 cells and then divided into two groups at random, including the Model group and Iso group. Mice in the Iso group were intraperitoneally injected with 25?mg/kg/d Iso, while mice in the Model group were supplied with the same amount of phosphate buffer saline (PBS, Beyotime). Tumor volume was monitored every 4 d. Mice were sacrificed with the intraperitoneal introduction of sodium pentobarbital (100 mg/kg) after tumor cells treatment for 31 d, and the tumor samples were removed and weighed. Tumor volume was determined according to the formula: volume = 1/2 x length x width². Click to Show/Hide
Response regulation	Isoliquiritin notably counteracted the LPS-induced relative protein levels of p-p50/p50, p-p65/p65 (RELA), and IB, and the levels of ferroptosis, oxidative stress, glycolysis, and inflammation. Iso inhibited the NF-kB signaling to regulate ferroptosis and improved Dox-resistance in breast cancer.

References

Ref 1	Lupeol triggers oxidative stress, ferroptosis, apoptosis and restrains inflammation in nasopharyngeal carcinoma via AMPK/NF-B pathway. Immunopharmacol Immunotoxicol. 2022 Aug;44(4):621-631. doi: 10.1080/08923973.2022.2072328. Epub 2022 May 16.
Ref 2	Isoliquiritin modulates ferroptosis via NF-B signaling inhibition and alleviates doxorubicin resistance in breast cancer. Immunopharmacol Immunotoxicol. 2023 Dec;45(4):443-454. doi: 10.1080/08923973.2023.2165943. Epub 2023 Jan 17.
Ref 3	Hesperidin mitigates oxidative stress-induced ferroptosis in nucleus pulposus cells via Nrf2/NF-B axis to protect intervertebral disc from degeneration. Cell Cycle. 2023 May;22(10):1196-1214. doi: 10.1080/15384101.2023.2200291. Epub 2023 Apr 13.
Ref 4	Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis. Cell Death Dis. 2020 Feb 3;11(2):86. doi: 10.1038/s41419-020-2299-1.

Ferroptosis Regulator Information

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Correspondence

Prof. Shuiping Liu