Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10005)
Regulator Name Toll-like receptor 4 (TLR4)
Synonyms
hToll; CD_antigen=CD284
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Gene Name TLR4
Gene ID 7099
Regulator Type Protein coding
Uniprot ID O00206
Sequence
MMSASRLAGTLIPAMAFLSCVRPESWEPCVEVVPNITYQCMELNFYKIPDNLPFSTKNLD
LSFNPLRHLGSYSFFSFPELQVLDLSRCEIQTIEDGAYQSLSHLSTLILTGNPIQSLALG
AFSGLSSLQKLVAVETNLASLENFPIGHLKTLKELNVAHNLIQSFKLPEYFSNLTNLEHL
DLSSNKIQSIYCTDLRVLHQMPLLNLSLDLSLNPMNFIQPGAFKEIRLHKLTLRNNFDSL
NVMKTCIQGLAGLEVHRLVLGEFRNEGNLEKFDKSALEGLCNLTIEEFRLAYLDYYLDDI
IDLFNCLTNVSSFSLVSVTIERVKDFSYNFGWQHLELVNCKFGQFPTLKLKSLKRLTFTS
NKGGNAFSEVDLPSLEFLDLSRNGLSFKGCCSQSDFGTTSLKYLDLSFNGVITMSSNFLG
LEQLEHLDFQHSNLKQMSEFSVFLSLRNLIYLDISHTHTRVAFNGIFNGLSSLEVLKMAG
NSFQENFLPDIFTELRNLTFLDLSQCQLEQLSPTAFNSLSSLQVLNMSHNNFFSLDTFPY
KCLNSLQVLDYSLNHIMTSKKQELQHFPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQL
LVEVERMECATPSDKQGMPVLSLNITCQMNKTIIGVSVLSVLVVSVVAVLVYKFYFHLML
LAGCIKYGRGENIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAA
NIIHEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKVEKTLLR
QQVELYRLLSRNTYLEWEDSVLGRHIFWRRLRKALLDGKSWNPEGTVGTGCNWQEATSI

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Family Toll-like receptor family
Function
Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific. Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression. In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor. Activated by the signaling pathway regulator NMI which acts as damage-associated molecular patterns (DAMPs) in response to cell injury or pathogen invasion, therefore promoting nuclear factor NF-kappa-B activation.

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HGNC ID
HGNC:11850
KEGG ID hsa:7099
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
TLR4 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
Unspecific Target [Unspecific Target]
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Responsed Disease Neuroinflammation ICD-11: 8C1Z
 Disease Info 
Responsed Drug Edaravone Approved
 Drug Info 
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model
 HT22 cells Normal Mus musculus CVCL_0321
Response regulation Edaravone could significantly reduce A1-42-induced apoptosis of HT22 cells and formation of pro-inflammatory factors TNF-, IL-1 and IL-6, prevent the activation of TLR4/NF-kB /NLRP3 signaling pathway, and inhibit ferroptosis and lipid peroxidation. Taken together, EDA contributes to inhibiting neuroinflammatory injury and ferroptosis in A 1-42-induced HT22 cells, and thus may be a potential candidate for the treatment of AD.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [5]
Responsed Disease Sepsis ICD-11: 1G40
 Disease Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vivo Model
Beijing Vital River Laboratory Animal Technology Co. Ltd. provided 20 specific pathogen-free female C57BL/6J mice (8-10 weeks old, weighing 20-22g). All procedures on mice were performed under sodium pentobarbital anesthesia, and all efforts were made to minimize suffering. 12 h after surgery, the blood was collected from orbital sinus.

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Response regulation 3 FRDEGs ( TLR4, WIPI1, and GABARAPL2), with high sensitivity and specificity in sepsis diagnosis, were selected for construction of prognostic risk signature. The expression of genes in risk signature was also validated in CLP mouse model via qRT-PCR.
NADPH oxidase 4 (NOX4) [Driver]
 Target Info 
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Driver
Responsed Disease Congestive heart failure ICD-11: BD10
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 rHTs (Rat hippocampal tissues)
In Vivo Model
Present animal studies used male Sprague Dawley rats (80-100 g) to create a HF model induced by the descending aortic banding (AB) procedure. The sham-operated (SO) group was defined as rats subjected to a similar procedure with the exception of arterial ligation. Echocardiography was applied to confirm the arterial banding immediately after the surgical procedure.

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Response regulation TLR4 or NOX4 knock-down significantly improved left ventricular remodeling and reduced myocytes death. Simultaneously, activated autophagy and ferroptosis in rats with heart failure (HF) were remarkably retarded by either TLR4 and NOX4 knock-down, suggesting TLR4-NOX4 as a potential therapeutic target for HF through inhibiting autophagy- and ferroptosis-mediated cell death.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [3]
Target for Ferroptosis Driver
Responsed Disease Ischemia/reperfusion injury ICD-11: DB98
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 HK-2 cells Normal Homo sapiens CVCL_0302
In Vivo Model
Adult male C57BL6 (C57) mice (8-12 weeks, 20-25 g) were purchased from the Animal Experiment Center of Wuhan University. All 64 mice were randomly divided into various groups by different treatments (n = 8). In sham group, after the right kidney excised, the left renal pedicles were without any treatment. In IRI group, the pedicle of the left kidney was clamped for 30 min followed by various reperfusion periods (6, 12, 24 h). To study the effects of LSD1, TCP (MedChemExpress) was injected intraperitoneally at different doses (2.5, 5, 10 mg/kg) before IRI model establishment, once a day for 1 week. TCP powder was dissolved in dimethyl sulfoxide (DMSO). In the vehicle control group, equal amount of DMSO was injected intraperitoneally.

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Response regulation LSD1 (KDM1A) inhibition blocked ferroptosis and oxidative stress caused by renal IRI through the TLR4/NOX4 pathway, indicating that LSD1 could be a potential therapeutic target for renal ischaemia reperfusion injury (IRI).
Cystine/glutamate transporter (SLC7A11) [Driver; 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 Preeclampsia ICD-11: JA24
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 hPTs (Human placental tissues)
Response regulation Panx1 and TLR4 are suggested to induce ferroptosis in Preeclampsia via SLC7A11-mediated signaling pathways, offering a novel perspective on PE pathogenesis and novel diagnostic tools for Preeclampsia.
Neuroinflammation [ICD-11: 8C1Z]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Toll-like receptor 4 (TLR4) Protein coding
 Regulator Info 
Responsed Drug Edaravone Approved
 Drug Info 
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model
 HT22 cells Normal Mus musculus CVCL_0321
Response regulation Edaravone could significantly reduce A1-42-induced apoptosis of HT22 cells and formation of pro-inflammatory factors TNF-, IL-1 and IL-6, prevent the activation of TLR4/NF-kB /NLRP3 signaling pathway, and inhibit ferroptosis and lipid peroxidation. Taken together, EDA contributes to inhibiting neuroinflammatory injury and ferroptosis in A 1-42-induced HT22 cells, and thus may be a potential candidate for the treatment of AD.
Congestive heart failure [ICD-11: BD10]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Toll-like receptor 4 (TLR4) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 rHTs (Rat hippocampal tissues)
In Vivo Model
Present animal studies used male Sprague Dawley rats (80-100 g) to create a HF model induced by the descending aortic banding (AB) procedure. The sham-operated (SO) group was defined as rats subjected to a similar procedure with the exception of arterial ligation. Echocardiography was applied to confirm the arterial banding immediately after the surgical procedure.

    Click to Show/Hide
Response regulation TLR4 or NOX4 knock-down significantly improved left ventricular remodeling and reduced myocytes death. Simultaneously, activated autophagy and ferroptosis in rats with heart failure (HF) were remarkably retarded by either TLR4 and NOX4 knock-down, suggesting TLR4-NOX4 as a potential therapeutic target for HF through inhibiting autophagy- and ferroptosis-mediated cell death.
Ischemia/reperfusion injury [ICD-11: DB98]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator Toll-like receptor 4 (TLR4) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 HK-2 cells Normal Homo sapiens CVCL_0302
In Vivo Model
Adult male C57BL6 (C57) mice (8-12 weeks, 20-25 g) were purchased from the Animal Experiment Center of Wuhan University. All 64 mice were randomly divided into various groups by different treatments (n = 8). In sham group, after the right kidney excised, the left renal pedicles were without any treatment. In IRI group, the pedicle of the left kidney was clamped for 30 min followed by various reperfusion periods (6, 12, 24 h). To study the effects of LSD1, TCP (MedChemExpress) was injected intraperitoneally at different doses (2.5, 5, 10 mg/kg) before IRI model establishment, once a day for 1 week. TCP powder was dissolved in dimethyl sulfoxide (DMSO). In the vehicle control group, equal amount of DMSO was injected intraperitoneally.

    Click to Show/Hide
Response regulation LSD1 (KDM1A) inhibition blocked ferroptosis and oxidative stress caused by renal IRI through the TLR4/NOX4 pathway, indicating that LSD1 could be a potential therapeutic target for renal ischaemia reperfusion injury (IRI).
Preeclampsia [ICD-11: JA24]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [4]
Target Regulator Toll-like receptor 4 (TLR4) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 hPTs (Human placental tissues)
Response regulation Panx1 and TLR4 are suggested to induce ferroptosis in Preeclampsia via SLC7A11-mediated signaling pathways, offering a novel perspective on PE pathogenesis and novel diagnostic tools for Preeclampsia.
Sepsis [ICD-11: 1G40]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [5]
Target Regulator Toll-like receptor 4 (TLR4) Protein coding
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vivo Model
Beijing Vital River Laboratory Animal Technology Co. Ltd. provided 20 specific pathogen-free female C57BL/6J mice (8-10 weeks old, weighing 20-22g). All procedures on mice were performed under sodium pentobarbital anesthesia, and all efforts were made to minimize suffering. 12 h after surgery, the blood was collected from orbital sinus.

    Click to Show/Hide
Response regulation 3 FRDEGs ( TLR4, WIPI1, and GABARAPL2), with high sensitivity and specificity in sepsis diagnosis, were selected for construction of prognostic risk signature. The expression of genes in risk signature was also validated in CLP mouse model via qRT-PCR.
Edaravone [Approved]
 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 Unspecific Target
Responsed Disease Neuroinflammation ICD-11: 8C1Z
 Disease Info 
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model
 HT22 cells Normal Mus musculus CVCL_0321
Response regulation Edaravone could significantly reduce A1-42-induced apoptosis of HT22 cells and formation of pro-inflammatory factors TNF-, IL-1 and IL-6, prevent the activation of TLR4/NF-kB /NLRP3 signaling pathway, and inhibit ferroptosis and lipid peroxidation. Taken together, EDA contributes to inhibiting neuroinflammatory injury and ferroptosis in A 1-42-induced HT22 cells, and thus may be a potential candidate for the treatment of AD.
References
Ref 1 Edaravone Attenuates A 1-42-Induced Inflammatory Damage and Ferroptosis in HT22 Cells. Neurochem Res. 2023 Feb;48(2):570-578. doi: 10.1007/s11064-022-03782-y. Epub 2022 Nov 4.
Ref 2 Role of TLR4/NADPH oxidase 4 pathway in promoting cell death through autophagy and ferroptosis during heart failure. Biochem Biophys Res Commun. 2019 Aug 13;516(1):37-43. doi: 10.1016/j.bbrc.2019.06.015. Epub 2019 Jun 10.
Ref 3 Lysine-specific demethylase 1 aggravated oxidative stress and ferroptosis induced by renal ischemia and reperfusion injury through activation of TLR4/NOX4 pathway in mice. J Cell Mol Med. 2022 Aug;26(15):4254-4267. doi: 10.1111/jcmm.17444. Epub 2022 Jun 30.
Ref 4 Novel insights into the SLC7A11-mediated ferroptosis signaling pathways in preeclampsia patients: identifying pannexin 1 and toll-like receptor 4 as innovative prospective diagnostic biomarkers. J Assist Reprod Genet. 2022 May;39(5):1115-1124. doi: 10.1007/s10815-022-02443-x. Epub 2022 Mar 24.
Ref 5 Identification of a Ferroptosis-Related Prognostic Signature in Sepsis via Bioinformatics Analyses and Experiment Validation. Biomed Res Int. 2022 May 25;2022:8178782. doi: 10.1155/2022/8178782. eCollection 2022.