General Information of the Ferroptosis Regulator (ID: REG10413)
Regulator Name Sphingosine kinase 1 (SPHK1)
Synonyms
Acetyltransferase SPHK1
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Gene Name SPHK1
Gene ID 8877
Regulator Type Protein coding
Uniprot ID Q9NYA1
Sequence
MDPAGGPRGVLPRPCRVLVLLNPRGGKGKALQLFRSHVQPLLAEAEISFTLMLTERRNHA
RELVRSEELGRWDALVVMSGDGLMHEVVNGLMERPDWETAIQKPLCSLPAGSGNALAASL
NHYAGYEQVTNEDLLTNCTLLLCRRLLSPMNLLSLHTASGLRLFSVLSLAWGFIADVDLE
SEKYRRLGEMRFTLGTFLRLAALRTYRGRLAYLPVGRVGSKTPASPVVVQQGPVDAHLVP
LEEPVPSHWTVVPDEDFVLVLALLHSHLGSEMFAAPMGRCAAGVMHLFYVRAGVSRAMLL
RLFLAMEKGRHMEYECPYLVYVPVVAFRLEPKDGKGVFAVDGELMVSEAVQGQVHPNYFW
MVSGCVEPPPSWKPQQMPPPEEPL

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Function
Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo- dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol. In contrast to proapoptotic SPHK2, has a negative effect on intracellular ceramide levels, enhances cell growth and inhibits apoptosis. Involved in the regulation of inflammatory response and neuroinflammation. Via the product sphingosine 1-phosphate, stimulates TRAF2 E3 ubiquitin ligase activity, and promotes activation of NF- kappa-B in response to TNF signaling leading to IL17 secretion. In response to TNF and in parallel to NF-kappa-B activation, negatively regulates RANTES induction through p38 MAPK signaling pathway. Involved in endocytic membrane trafficking induced by sphingosine, recruited to dilate endosomes, also plays a role on later stages of endosomal maturation and membrane fusion independently of its kinase activity. In Purkinje cells, seems to be also involved in the regulation of autophagosome-lysosome fusion upon VEGFA.; Has serine acetyltransferase activity on PTGS2/COX2 in an acetyl-CoA dependent manner. The acetyltransferase activity increases in presence of the kinase substrate, sphingosine. During neuroinflammation, through PTGS2 acetylation, promotes neuronal secretion of specialized preresolving mediators (SPMs), especially 15- R-lipoxin A4, which results in an increase of phagocytic microglia.

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HGNC ID
HGNC:11240
KEGG ID hsa:8877
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
SPHK1 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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Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Cerebral ischemia ICD-11: 8B10
Responsed Drug Dihydromyricetin Investigative
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
HT22 cells Normal Mus musculus CVCL_0321
In Vivo Model
Rats were anesthetized by pentobarbital sodium at a dosage of 40 mg/kg by intraperitoneal injection. Rats were first anchored on to an operating table in the supine position. The fur around the incision was shaved and then disinfected. Subsequently, the neck of each rat was incised in the middle to expose the right common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA). The proximal end of the CCA and ECA were ligated and severed using a 0.285 mm nylon suture. The suture was inserted from the ECA stump through the ICA to reach the MCA. The MCA was then occluded for 2 h to create ischemic conditions. Next, the nylon suture was slowly pulled out to restore blood flow and simulate reperfusion condition.

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Response regulation Dihydromyricetin (DHM) repressed ferroptosis by inhibiting the SPHK1/mTOR signaling pathway, thereby alleviating cerebral ischemia reperfusion injury. Moreover, the expression levels of glutathione peroxidase 4 (GPX4) was enhanced while the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and phosphatidylethanolamine binding protein 1 (PEBP1) were reduced in OGD/R-treated HT22 cells in the presence of DHM.
Cerebral ischemia [ICD-11: 8B10]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Sphingosine kinase 1 (SPHK1) Protein coding
Responsed Drug Dihydromyricetin Investigative
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
HT22 cells Normal Mus musculus CVCL_0321
In Vivo Model
Rats were anesthetized by pentobarbital sodium at a dosage of 40 mg/kg by intraperitoneal injection. Rats were first anchored on to an operating table in the supine position. The fur around the incision was shaved and then disinfected. Subsequently, the neck of each rat was incised in the middle to expose the right common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA). The proximal end of the CCA and ECA were ligated and severed using a 0.285 mm nylon suture. The suture was inserted from the ECA stump through the ICA to reach the MCA. The MCA was then occluded for 2 h to create ischemic conditions. Next, the nylon suture was slowly pulled out to restore blood flow and simulate reperfusion condition.

    Click to Show/Hide
Response regulation Dihydromyricetin (DHM) repressed ferroptosis by inhibiting the SPHK1/mTOR signaling pathway, thereby alleviating cerebral ischemia reperfusion injury. Moreover, the expression levels of glutathione peroxidase 4 (GPX4) was enhanced while the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and phosphatidylethanolamine binding protein 1 (PEBP1) were reduced in OGD/R-treated HT22 cells in the presence of DHM.
Dihydromyricetin [Investigative]
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Suppressor
Response Target Phospholipid hydroperoxide glutathione peroxidase (GPX4) Suppressor
Responsed Disease Cerebral ischemia ICD-11: 8B10
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
HT22 cells Normal Mus musculus CVCL_0321
In Vivo Model
Rats were anesthetized by pentobarbital sodium at a dosage of 40 mg/kg by intraperitoneal injection. Rats were first anchored on to an operating table in the supine position. The fur around the incision was shaved and then disinfected. Subsequently, the neck of each rat was incised in the middle to expose the right common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA). The proximal end of the CCA and ECA were ligated and severed using a 0.285 mm nylon suture. The suture was inserted from the ECA stump through the ICA to reach the MCA. The MCA was then occluded for 2 h to create ischemic conditions. Next, the nylon suture was slowly pulled out to restore blood flow and simulate reperfusion condition.

    Click to Show/Hide
Response regulation Dihydromyricetin (DHM) repressed ferroptosis by inhibiting the SPHK1/mTOR signaling pathway, thereby alleviating cerebral ischemia reperfusion injury. Moreover, the expression levels of glutathione peroxidase 4 (GPX4) was enhanced while the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and phosphatidylethanolamine binding protein 1 (PEBP1) were reduced in OGD/R-treated HT22 cells in the presence of DHM.
References
Ref 1 Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis. Drug Des Devel Ther. 2022 Sep 11;16:3071-3085. doi: 10.2147/DDDT.S378786. eCollection 2022.