Affinage

SPHK1

Sphingosine kinase 1 · UniProt Q9NYA1

Length
384 aa
Mass
42.5 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPHK1 is a lipid kinase that produces sphingosine-1-phosphate (S1P) and thereby sets the cellular sphingolipid rheostat, opposing SphK2 such that SphK1 lowers ceramide while its product S1P drives pro-survival, pro-migratory, and angiogenic programs (PMID:16118219). Its biological output is dictated by where S1P is made: targeting SphK1 to the endoplasmic reticulum converts it from anti-apoptotic to pro-apoptotic (PMID:16118219), whereas signal-induced translocation to the plasma membrane couples S1P production to receptor signaling (PMID:15741218, PMID:35358930). Upstream, SphK1 is activated by growth-factor and stress receptors—VEGF acts through VEGFR2/PKC/ERK1/2 to drive membrane targeting and angiogenesis (PMID:35358930, PMID:25417698), IGF-I/insulin through PI3K/Akt and ERK (PMID:17388800, PMID:24422628), and TLR4 induces S225 phosphorylation and membrane translocation to engage S1PR4/ERK/matriptase in cancer invasion (PMID:31152147). SphK1 is also a PKR substrate that feeds back to inhibit PKR autophosphorylation and antagonize apoptosis (PMID:32801355). Its expression is transcriptionally controlled by Egr-1, Lmo2, FoxO3, and HIF (PMID:27099350, PMID:28775072, PMID:34051800, PMID:30655321) and post-transcriptionally by m6A methylation via ALKBH5/METTL3 (PMID:35127873). Downstream, SphK1/S1P signaling activates NF-κB-driven cyclin D1 and NRF2 programs (PMID:27811358, PMID:39875359), STAT/Akt/SIRT1 and Akt survival axes (PMID:26923291, PMID:25680461, PMID:34873055), and ERK1/2- and NLRP3-linked inflammatory outputs (PMID:39715736, PMID:40665874), controlling cell survival, proliferation, migration/EMT, autophagy (PMID:38135696, PMID:27467777), angiogenesis (PMID:28775072, PMID:38200582), immune cell function (PMID:31971297, PMID:33566377), ER-stress/mitochondrial injury (PMID:31827236), and oocyte meiotic competence (PMID:36396932). Genetic deletion studies in mice establish SphK1 as a driver of inflammatory liver injury (PMID:31827236, PMID:33566377) and as essential, in somatic cells, for female fertility (PMID:36396932).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2005 High

    Established that S1P function is determined by where SphK1 acts, resolving how a single product can be both pro- and anti-apoptotic and defining the SphK1/SphK2 ceramide rheostat.

    Evidence siRNA knockdown, adenoviral overexpression, MS/MS lipidomics, and ER-targeting constructs in mammalian cells

    PMID:16118219

    Open questions at the time
    • Did not map endogenous SphK1 trafficking signals
    • Mechanism converting ER-localized S1P to a pro-apoptotic signal not defined
  2. 2004 High

    Showed SphK1 is a transcriptionally inducible effector linking TGF-β to extracellular matrix remodeling via AP1/c-Jun-driven TIMP-1.

    Evidence siRNA, adenoviral overexpression, TIMP-1 promoter-reporter and SphK activity assays in dermal fibroblasts

    PMID:15485866

    Open questions at the time
    • Did not identify the S1P target linking SphK1 to c-Jun phosphorylation
  3. 2005 Medium

    Demonstrated that plasma-membrane-restricted S1P production can desensitize surface S1P receptors, revealing a negative-feedback dimension to SphK1 signaling.

    Evidence Confocal imaging, G-protein coupling and S1P receptor internalization assays in RBL-2H3 mast cells

    PMID:15741218

    Open questions at the time
    • Single cell type
    • Did not identify the membrane-targeting trigger at the molecular level
  4. 2013 Medium

    Defined receptor-specific phosphorylation inputs, showing SphK1 (but not SphK2) responds to insulin receptor as well as IGF1R, with S1PR3 required for mitogenesis.

    Evidence Phosphorylation and isoform-specific knockdown with receptor inhibitors in MCF7 cells

    PMID:24422628

    Open questions at the time
    • Kinase phosphorylating SphK1 downstream of insulin receptor not identified
  5. 2010 Medium

    Extended SphK1 function to innate immunity, identifying it as a regulator of p38 MAPK, iNOS/NO, and lysosomal LAMP-2 in macrophage antimicrobial defense.

    Evidence siRNA, overexpression, competitive inhibitor and NO measurement in infected macrophages

    PMID:20498849

    Open questions at the time
    • S1P receptor/intracellular target mediating p38 activation not defined
  6. 2016 High

    Identified multiple transcription factors—Egr-1, Lmo2, FoxO3—that bind the SphK1 promoter directly, defining how distinct stimuli converge on SphK1 transcription in vascular and ischemic contexts.

    Evidence ChIP-PCR, EMSA, luciferase reporters, siRNA, and zebrafish mRNA rescue across PASMC, endothelial, and ischemia models

    PMID:27099350 PMID:28775072 PMID:34051800

    Open questions at the time
    • Whether these factors act combinatorially on the same promoter not addressed
    • Cell-type specificity of each factor not resolved
  7. 2016 Medium

    Connected SphK1 to specific downstream transcriptional and signaling effectors—NF-κB-p65/cyclin D1, SIRT1, and FAK/EMT markers—linking it to proliferation and migration.

    Evidence ChIP, NF-κB inhibition, pathway inhibitors, and pharmacological SphK1/FAK inhibition in breast, endothelial, and colorectal cells

    PMID:26923291 PMID:27811358 PMID:28405684

    Open questions at the time
    • Direct molecular link between S1P and NF-κB/FAK activation not reconstituted
    • Receptor vs intracellular S1P target not distinguished
  8. 2014 High

    Placed SphK1 in autophagic flux and neuronal survival, showing VEGF/VEGFR2-driven SphK1 activity rescues sphingosine storage and autophagosome-lysosome fusion in Niemann-Pick type C neurons.

    Evidence iPSC-derived NP-C neurons, VEGFR2 activation and SphK activity assays, Purkinje survival in NP-C mice

    PMID:25417698

    Open questions at the time
    • How S1P controls autophagosome-lysosome fusion mechanistically not defined
  9. 2019 High

    Genetic knockout established SphK1 as a driver of organ injury, mediating ER stress and mitochondrial permeability transition in liver and S1PR4-dependent invasion in cancer.

    Evidence Sphk1 knockout mice with S1P rescue, pharmacological inhibition, phospho-SphK1 western blot and patient-derived explant models

    PMID:30655321 PMID:31152147 PMID:31827236

    Open questions at the time
    • How S1P engages IRE1α/PERK/ATF6 ER-stress arms not mechanistically resolved
  10. 2020 Medium

    Revealed a bidirectional SphK1-PKR relationship: SphK1 is a PKR substrate whose product drives survival signaling, while SphK1 binds latent PKR to block its dimerization, creating an apoptosis-antagonizing feedback loop.

    Evidence Co-immunoprecipitation, kinase activity assays, and mutagenesis

    PMID:32801355

    Open questions at the time
    • Binding interface not structurally defined
    • Single-lab interaction without reciprocal in vivo confirmation
  11. 2021 High

    Dissected receptor-proximal signaling that recruits SphK1, showing aPC/PAR1 uses a β-arrestin-2 pathway to activate SphK1 and transactivate S1PR1 in caveolin-1 microdomains for endothelial survival.

    Evidence Reciprocal endogenous Co-IP, multiplexed siRNA, and apoptosis assays in human endothelial cells

    PMID:34873055

    Open questions at the time
    • Mechanism of SphK1 recruitment to caveolin-1 microdomains not defined
  12. 2021 High

    Defined the immune-cell-intrinsic role of SphK1 in inflammation, showing it operates in infiltrating myeloid cells to drive TNFα/NF-κB liver injury and is required for TLR7/9-dependent type I interferon in pDCs.

    Evidence SphK1/SphK2 knockout mice, adoptive bone marrow transfer, lupus models and pDC functional assays

    PMID:31971297 PMID:33566377

    Open questions at the time
    • Molecular basis of SphK1-TLR7/9 functional interaction not resolved
    • S1P receptor mediating cytokine output not pinned down
  13. 2022 High

    Established post-transcriptional and translocation control of SphK1 and its essential role in reproduction, including m6A regulation and somatic-cell SphK requirement for oocyte competence.

    Evidence ALKBH5/METTL3 manipulation with m6A assays, VEGFR2/PKC/ERK Co-IP and imaging, conditional Sphk1/2 knockout in ovarian somatic cells with S1P rescue

    PMID:35127873 PMID:35358930 PMID:36396932

    Open questions at the time
    • m6A reader linking methylation to SphK1 fate not identified
    • How somatic-cell S1P transmits to the oocyte at the receptor level not fully resolved
  14. 2024 Medium

    Linked SphK1 to metabolic and cell-death rewiring in cancer and vascular injury—PFKFB3 glycolytic control, NF-κB/NRF2 ferroptosis resistance, NLRP3 pyroptosis/inflammasome, and TRAF6/ULK1 autophagy.

    Evidence PF-543 inhibition, Sphk1 knockout/knockdown, co-IP, proteasomal degradation and S1P-receptor rescue across HCC, ovarian and colorectal models

    PMID:38135696 PMID:38200582 PMID:39715736 PMID:39875359 PMID:40665874

    Open questions at the time
    • Mechanisms remain individually single-lab
    • Whether these outputs share a common S1P-receptor or intracellular target not unified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the spatial code of S1P production—membrane vs ER vs autophagic/endosomal SphK1 pools—is read out into opposing cell fates remains the central unresolved question.
  • No structural model of SphK1 in different membrane microdomains
  • Intracellular S1P targets distinct from surface S1P receptors largely uncharacterized
  • Quantitative relationship between local S1P/ceramide balance and fate decisions not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0008289 lipid binding 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 3 R-HSA-1430728 Metabolism 2
Partners
PAR1PKRS1PR1TLR4TLR7TLR9TRAF6VEGFR2

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 SphK1 and SphK2 have opposing roles in ceramide biosynthesis: SphK1 decreases ceramide levels while SphK2 increases them. Targeting SphK1 to the endoplasmic reticulum converts it from anti-apoptotic to pro-apoptotic, demonstrating that the subcellular location of S1P production dictates its function. Down-regulation of SphK1 increased conversion of sphingosine to ceramide in the recycling pathway. siRNA knockdown, adenoviral overexpression, electrospray ionization MS/MS lipidomics, subcellular targeting constructs, [3H]palmitate incorporation assay The Journal of biological chemistry High 16118219
2004 TGF-β markedly up-regulates SphK1 mRNA and protein and causes a prolonged increase in SphK activity in dermal fibroblasts, leading to increased S1P and decreased sphingosine/ceramide. SphK1 mediates TGF-β-induced TIMP-1 up-regulation via the AP1-response element on the TIMP-1 promoter, as shown by SphK1 siRNA knockdown blocking TIMP-1 induction and ectopic SphK1 increasing phospho-c-Jun levels. siRNA knockdown, adenoviral SphK1 overexpression, TIMP-1 promoter-reporter constructs, SphK activity assay, sphingolipid quantification The Journal of biological chemistry High 15485866
2005 Overexpression of SphK1 in RBL-2H3 mast cells impaired degranulation and migration toward antigen in the presence of serum. Serum increased localization of SphK1 at the plasma membrane, and membrane-restricted S1P production induced internalization and desensitization of surface S1P receptors, uncoupling them from G proteins, which abrogated downstream signaling. Confocal immunofluorescence microscopy, G-protein coupling assay, S1P receptor internalization assay, SphK1 overexpression Blood Medium 15741218
2007 IGFBP-3 induces angiogenesis in endothelial cells through IGF-I–activated SphK1 (requiring PI3K/Akt and ERK1/2 signaling upstream of SphK1), and SphK1 siRNA knockdown blocks IGFBP-3–induced network formation and VEGF/MT1-MMP up-regulation. siRNA knockdown, Matrigel tube formation assay, SphK activity assay, pathway inhibitor experiments, in vivo Matrigel plug assay Journal of thrombosis and haemostasis Medium 17388800
2010 SphK1 confers resistance to Mycobacterium smegmatis infection in macrophages by enhancing NO generation, iNOS expression, p38 MAPK activation, and LAMP-2 expression; selective inhibition or siRNA knockdown of SphK1 renders macrophages sensitive to infection. SphK1 was identified as a novel regulator of p38 MAPK in this context. SphK1 siRNA knockdown, SphK1 overexpression, competitive inhibitor (DHS), NO measurement, western blotting PloS one Medium 20498849
2014 In Niemann-Pick type C (NP-C) neurons, SphK1 activity is reduced due to defective VEGF signaling via VEGFR2; VEGF activates SphK1 by binding VEGFR2, reducing sphingosine storage and restoring Purkinje neuron survival. Defective SphK1 activity leads to impaired autophagosome-lysosome fusion and Purkinje neuron loss. iPSC-derived human NP-C neurons, VEGFR2 activation assay, SphK activity assay, Purkinje neuron survival analysis in NP-C mice Nature communications High 25417698
2015 The SphK1 activator K6PC-5 activates SphK1, increases intracellular S1P, and induces Akt phosphorylation in osteoblasts, protecting them from dexamethasone-induced apoptosis and necrosis. SphK1 inhibitors (DMS) or SphK1-siRNA abolished these protective effects, placing SphK1 upstream of Akt in osteoblast survival signaling. SphK1 siRNA knockdown, SphK1 activator (K6PC-5), SphK1 inhibitor (DMS), Akt phosphorylation western blot, cell viability assay Biochemical and biophysical research communications Medium 25680461
2016 PDGF induces SphK1 expression in pulmonary artery smooth muscle cells (PASMCs) via the transcription factor Egr-1 downstream of ERK signaling; ChIP confirmed direct Egr-1 binding to the SphK1 promoter, and Egr-1 silencing reduced PDGF-induced SphK1 expression and PASMC proliferation. Chromatin immunoprecipitation (ChIP-PCR), luciferase reporter assay, SphK1 promoter truncation, siRNA knockdown, ERK inhibition American journal of physiology. Cell physiology High 27099350
2016 SphK1 modulates EMT marker expression and colorectal cancer cell migration by regulating phospho-FAK (p-FAK); SphK1 inhibition reduces p-FAK expression and decreases Slug, vimentin, N-cadherin while increasing E-cadherin, and FAK inhibition phenocopies SphK1 inhibition. SphK1 inhibitor (SKI-II), FAK inhibitor (PF-562271), western blot, Transwell migration assay, PCR International journal of molecular medicine Medium 28405684
2016 Sphk1 promotes breast epithelial cell proliferation via NF-κB-p65-mediated cyclin D1 expression; Sphk1 overexpression induces NF-κB-p65 activation, and ChIP assays confirmed NF-κB-p65 binding to the cyclin D1 promoter. ChIP assay, NF-κB inhibitor, western blot, Sphk1 overexpression (MCF10A cells), cell cycle analysis Oncotarget Medium 27811358
2016 SphK1/S1P up-regulates SIRT1 through P38 MAPK, ERK, and AKT signaling pathways to regulate endothelial cell proliferation and migration; SphK1 knockdown reduces SIRT1 expression, and exogenous S1P reverses this. siRNA knockdown, CCK8 proliferation assay, Transwell migration assay, pathway inhibitors (PD98059, SB203580, Wortmannin), western blot The international journal of biochemistry & cell biology Medium 26923291
2017 Lmo2 transcription factor directly binds the Sphk1 promoter (confirmed by ChIP-PCR) to drive Sphk1 gene expression in endothelial cells; Lmo2 knockdown reduces Sphk1 expression and impairs endothelial cell migration and intersegmental vessel formation in zebrafish, phenotypes rescued by Sphk1 mRNA. ChIP-PCR, mRNA rescue experiments, Lmo2 and Sphk1 knockdown in zebrafish Tg(fli1:EGFP), scratch migration assay, BrdU immunostaining Arteriosclerosis, thrombosis, and vascular biology High 28775072
2019 LPS activates SphK1 via TLR4, inducing S225 phosphorylation of SphK1 and translocation to the plasma membrane, leading to S1P production and activation of ERK1/2 and matriptase via S1P receptor 4 (S1PR4), which promotes prostate cancer cell invasion. Biochemical analysis, protease inhibitor screening, S1PR4 pathway analysis, phospho-SphK1 western blot, patient-derived explant (PDE) model validation Oncogene Medium 31152147
2019 SPHK1 deficiency protects mice from acetaminophen-induced liver injury by alleviating ER stress (affecting IRE1α phosphorylation, PERK-eIF2α-ATF4 pathway, ATF6 activation) and inhibiting mitochondrial permeability transition (MPT) via impaired JNK, ASK1, and GSK3β phosphorylation. Exogenous S1P reversed PERK-eIF2α-ATF4 and GSK3β/ASK1/JNK activation, confirming S1P as the mediating signal. Sphk1 knockout mice, S1P supplementation rescue, SPHK1 inhibitor (PF543) and S1P receptor antagonist (FTY720), western blot for ER stress and MPT markers Cell death and differentiation High 31827236
2019 SPHK1 overexpression promotes ovarian cancer cell proliferation, migration, invasion, and stem-like phenotypes. Metformin blocks hypoxia-induced SPHK1 expression by inhibiting nuclear translocation of HIF1α and HIF2α, thereby reducing S1P levels. Xenograft model, lipidomics, SPHK1 overexpression, siRNA knockdown, HIF inhibition Molecular cancer research Medium 30655321
2016 FoxO3 transcription factor directly binds the SPHK1 promoter and activates its transcription during cerebral ischemia/reperfusion; EMSA and ChIP confirmed the FoxO3–SPHK1 promoter interaction, and FoxO3 knockdown suppressed SPHK1-mediated inflammation and cell death. EMSA, ChIP, dual luciferase assay, siRNA knockdown, MCAO/reperfusion rat model and OGD/R cell model Journal of neuroinflammation Medium 34051800
2021 SphK1 interacts with TLR7/9 in plasmacytoid dendritic cells (pDCs) and is required for TLR7/9-dependent type I interferon production and pro-inflammatory cytokine responses; specific SphK1 deletion or inhibition in pDCs mitigates uptake of CpG oligonucleotide ligands and decreases IFN signature in a lupus model. SphK1 knockout mice, pharmacological SphK1 inhibition, pristane-induced lupus model, pDC functional assays FASEB journal Medium 31971297
2020 SPHK1 is a substrate of PKR; phosphorylated SPHK1 activates pro-survival S1P/S1PR1/MAPKs/IKKα signaling and also acts as a negative feedback regulator by binding to the latent form of PKR at the C-terminal kinase motif, inhibiting PKR homodimerization and autophosphorylation, thereby antagonizing PKR-mediated apoptosis. Phosphorylation interplay assays, direct binding/co-immunoprecipitation, kinase activity assays, mutagenesis approaches Cell death and differentiation Medium 32801355
2021 Activated protein C (aPC)/PAR1 signals via a discrete β-arrestin-2–mediated pathway to activate SphK1, which produces S1P that transactivates S1PR1 within caveolin-1-rich microdomains, activating Akt to protect endothelial cells from apoptosis. This pathway is distinct from the β-arrestin-2/Dvl2 pathway used for barrier protection, and requires caveolin-1. Endogenous PAR1/S1PR1 co-immunoprecipitation, siRNA knockdown of β-arrestin-2/SphK1/S1PR1/Cav1, Akt phosphorylation assay, apoptosis assay in human endothelial cells Proceedings of the National Academy of Sciences High 34873055
2021 Deletion of SphK1 (but not SphK2) dramatically decreases GalN/LPS-induced liver damage, NF-κB and JNK activation, and TNFα production. Adoptive transfer established that SphK1 in bone marrow-derived infiltrating immune cells (not liver-resident cells) drives acute liver failure; SphK1-deleted macrophages produce markedly less TNFα and more IL-10 upon LPS stimulation. SphK1 and SphK2 knockout mice, adoptive bone marrow transfer, specific SphK1 inhibitor treatment, cytokine ELISA, western blot FASEB journal High 33566377
2022 ALKBH5 (m6A RNA demethylase) maintains SPHK1 protein levels by reducing SPHK1 mRNA m6A methylation; ALKBH5 silencing increased SPHK1 m6A mRNA methylation and reduced SPHK1 expression, impairing eNOS phosphorylation and ischemia-induced endothelial cell angiogenesis. METTL3 overexpression similarly reduced SPHK1 expression. siRNA ALKBH5 knockdown, METTL3 overexpression, m6A methylation assay, eNOS phosphorylation western blot, tube formation assay Frontiers in cardiovascular medicine Medium 35127873
2022 SphK1 translocation to the plasma membrane is activated via the VEGFR2/PKC/ERK1/2 pathway; co-immunoprecipitation and confocal microscopy confirmed SphK1 membrane targeting is closely linked to VEGF-stimulated endothelial cell biological functions and angiogenesis, and SphK1 siRNA knockdown attenuated these effects in vitro and in vivo. Co-immunoprecipitation, laser scanning confocal microscopy, SphK1-siRNA transfection, Matrigel plug assay in mice, tube formation assay Phytomedicine Medium 35358930
2022 SphK-produced S1P in ovarian somatic cells (granulosa/cumulus cells) acts as a functional transmitter of LH-EGFR signaling to oocytes: S1P increases calcium in cumulus-oocyte complexes, decreases NPR2 binding affinity for NPPC to release cGMP-mediated meiotic arrest, and activates Akt/mTOR in oocytes to improve developmental competence. Depleting Sphk1/2 specifically in somatic cells causes complete female infertility. Conditional Sphk1/2 double knockout in somatic cells, S1P supplementation rescue, SphK inhibitor (SKI-II) treatment, calcium measurement, cGMP measurement, NPR2 binding assay Cell death & disease High 36396932
2013 Both SphK1 and SphK2 mediate insulin's mitogenic action in MCF7 breast cancer cells, with phosphorylation of SphK1 being mediated by both insulin receptor and IGF1R, while SphK2 phosphorylation is mediated only by IGF1R; S1P receptor 3 (S1PR3) is required for insulin-mediated mitogenic action downstream of SphKs. SphK1/2 phosphorylation assay, isoform-specific knockdown, pathway inhibitors, cell cycle and proliferation assays Molecular endocrinology Medium 24422628
2016 C5a/C5aR pathway up-regulates SphK1 expression through p38-MAPK activation in acute liver failure; C5aR blockade reduced p38-MAPK phosphorylation in liver tissue and C5a-stimulated macrophages, and p38-MAPK inhibition (SB203580) significantly reduced SphK1 protein production downstream of C5a stimulation. C5aR antagonist treatment, p38-MAPK inhibitor (SB203580), western blot for p38/p-p38/SphK1, ALF mouse model World journal of gastroenterology Medium 28028363
2021 SPHK1 drives colorectal cancer metastasis via autophagy through TRAF6-induced ULK1 ubiquitination; SPHK1 physically interacts with TRAF6 (confirmed by co-immunoprecipitation and co-localization), and SPHK1 knockdown reduces TRAF6 and autophagy, while TRAF6 overexpression reverses these effects. Autophagy inhibitor 3-MA suppresses the metastasis-promoting effect of both SPHK1 and TRAF6. Co-immunoprecipitation, immunofluorescence co-localization, siRNA/overexpression double-gene transfection, proteasome inhibitor (MG132) treatment, 3-MA autophagy inhibition Cancer gene therapy Medium 38135696
2024 SphK1 promotes Nlrp3-mediated pyroptosis of brain endothelial cells via the ERK1/2 signaling pathway, causing blood-brain barrier breakdown after intracerebral hemorrhage; pharmacological inhibition of SphK1 with PF543 preserved tight junction proteins, suppressed endothelial transcytosis, and reduced hematoma volume in mice. PF543 pharmacological inhibition, siRNA knockdown, tight junction protein western blot, electron microscopy of BBB ultrastructure, ERK1/2 pathway analysis Cell death & disease Medium 39715736
2024 SphK1/S1P produced by tumor-associated macrophages (TAMs) activates the NLRP3 inflammasome and IL-1β release via NF-κB and HIF-1α signaling in an autocrine manner; paracrine IL-1β then upregulates ADAM17 in CRC cells, driving CD8+ T cell exhaustion and immunosuppressive tumor microenvironment in colorectal cancer liver metastasis. RNA-sequencing, SPHK1 knockout/knockdown in macrophages, NLRP3 inflammasome assay, cytokine measurements, co-culture assays, flow cytometry, in vivo mouse models Cancer communications Medium 40665874
2024 SphK1 inhibition by PF-543 induces proteasomal degradation of the glycolytic enzyme PFKFB3, restricting the energy supply essential for tumor angiogenesis in hepatocellular carcinoma; this effect is reversed by exogenous S1P in an S1P receptor-dependent manner, linking SphK1 activity to glycolytic regulation in endothelial cells. PF-543 treatment, Sphk1 knockout mice, diethylnitrosamine-induced primary HCC mouse model, lentiviral SphK1 knockdown, PFKFB3 proteasomal degradation assay, S1P rescue experiments Journal of translational medicine Medium 38200582
2024 SPHK1 promotes olaparib resistance in ovarian cancer by activating NF-κB through p-IκBα degradation, which in turn transcriptionally upregulates NRF2 to inhibit ferroptosis; SPHK1 inhibition (PF-543) triggers ferroptosis by restricting NF-κB-activated NRF2 transcription. SPHK1 siRNA knockdown, PF-543 inhibitor, NF-κB p65 pathway analysis, NRF2 transcription assay, ferroptosis inducers (erastin/RSL3), xenograft models Cell death discovery Medium 39875359
2016 SphK1 knockdown in neuronal cells during autophagy stimulation causes SphK1 to relocalize to endocytic and autophagic organelles (endosomes, autophagosomes, amphisomes), distinct from growth factor-stimulated translocation to the plasma membrane in non-neuronal cells; a dominant-negative SphK1 was toxic to SH-SY5Y cells but tolerated in primary cortical neurons. Live-cell fluorescence imaging, organelle marker co-localization, dominant-negative SphK1 expression, amino acid deprivation-induced autophagy Autophagy Medium 27467777

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. The Journal of biological chemistry 529 16118219
2008 Targeting SphK1 as a new strategy against cancer. Current drug targets 276 18691013
2015 LncRNA Khps1 Regulates Expression of the Proto-oncogene SPHK1 via Triplex-Mediated Changes in Chromatin Structure. Molecular cell 260 26590717
2016 Downregulated miR-506 expression facilitates pancreatic cancer progression and chemoresistance via SPHK1/Akt/NF-κB signaling. Oncogene 144 27065335
2004 Sphingosine kinase 1 (SPHK1) is induced by transforming growth factor-beta and mediates TIMP-1 up-regulation. The Journal of biological chemistry 127 15485866
2004 Non-coding RNA directed DNA demethylation of Sphk1 CpG island. Biochemical and biophysical research communications 118 15325271
2007 Insulin-like growth factor binding protein-3 induces angiogenesis through IGF-I- and SphK1-dependent mechanisms. Journal of thrombosis and haemostasis : JTH 99 17388800
2021 miR-19a/b-3p promotes inflammation during cerebral ischemia/reperfusion injury via SIRT1/FoxO3/SPHK1 pathway. Journal of neuroinflammation 81 34051800
2017 Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget. Oncotarget 81 28415564
2014 Importance of sphingosine kinase (SphK) as a target in developing cancer therapeutics and recent developments in the synthesis of novel SphK inhibitors. Journal of medicinal chemistry 81 24471412
2013 Structure guided design of a series of sphingosine kinase (SphK) inhibitors. Bioorganic & medicinal chemistry letters 81 23845219
2019 SPHK1 deficiency protects mice from acetaminophen-induced ER stress and mitochondrial permeability transition. Cell death and differentiation 72 31827236
2018 MicroRNA‑125b regulates Alzheimer's disease through SphK1 regulation. Molecular medicine reports 71 29901156
2022 Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis. Drug design, development and therapy 70 36118165
2019 SPHK1 Is a Novel Target of Metformin in Ovarian Cancer. Molecular cancer research : MCR 69 30655321
2014 SPHK1 regulates proliferation and survival responses in triple-negative breast cancer. Oncotarget 65 25153718
2018 Quercetin ameliorates pulmonary fibrosis by inhibiting SphK1/S1P signaling. Biochemistry and cell biology = Biochimie et biologie cellulaire 63 29940125
2017 miR-613 inhibits bladder cancer proliferation and migration through targeting SphK1. American journal of translational research 63 28386347
2011 An novel role of sphingosine kinase-1 (SPHK1) in the invasion and metastasis of esophageal carcinoma. Journal of translational medicine 63 21936950
2014 Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons. Nature communications 60 25417698
2024 The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target. Cancer cell international 55 38419070
2015 K6PC-5, a novel sphingosine kinase 1 (SphK1) activator, alleviates dexamethasone-induced damages to osteoblasts through activating SphK1-Akt signaling. Biochemical and biophysical research communications 55 25680461
2021 Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases. Frontiers in pharmacology 52 34737701
2017 SphK1 modulates cell migration and EMT-related marker expression by regulating the expression of p-FAK in colorectal cancer cells. International journal of molecular medicine 52 28405684
2005 Expression of SphK1 impairs degranulation and motility of RBL-2H3 mast cells by desensitizing S1P receptors. Blood 52 15741218
2022 Atractylenolide-1 targets SPHK1 and B4GALT2 to regulate intestinal metabolism and flora composition to improve inflammation in mice with colitis. Phytomedicine : international journal of phytotherapy and phytopharmacology 51 35114452
2018 TRIM14 promotes colorectal cancer cell migration and invasion through the SPHK1/STAT3 pathway. Cancer cell international 47 30555277
2015 SphK1 inhibitor II (SKI-II) inhibits acute myelogenous leukemia cell growth in vitro and in vivo. Biochemical and biophysical research communications 45 25824043
2021 Geniposide downregulates the VEGF/SphK1/S1P pathway and alleviates angiogenesis in rheumatoid arthritis in vivo and in vitro. Phytotherapy research : PTR 44 34152633
2022 Geniposide alleviates VEGF-induced angiogenesis by inhibiting VEGFR2/PKC/ERK1/2-mediated SphK1 translocation. Phytomedicine : international journal of phytotherapy and phytopharmacology 41 35358930
2022 miR-495-3p regulates sphingolipid metabolic reprogramming to induce Sphk1/ceramide mediated mitophagy and apoptosis in NSCLC. Free radical biology & medicine 41 35853537
2016 PDGF induces SphK1 expression via Egr-1 to promote pulmonary artery smooth muscle cell proliferation. American journal of physiology. Cell physiology 41 27099350
2015 SphK1 promotes tumor cell migration and invasion in colorectal cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 41 26662312
2016 SIRT1 mediates Sphk1/S1P-induced proliferation and migration of endothelial cells. The international journal of biochemistry & cell biology 40 26923291
2019 Activation of sphingosine kinase by lipopolysaccharide promotes prostate cancer cell invasion and metastasis via SphK1/S1PR4/matriptase. Oncogene 39 31152147
2016 Tumor suppressor PRSS8 targets Sphk1/S1P/Stat3/Akt signaling in colorectal cancer. Oncotarget 39 27050145
2020 Targeting the SphK-S1P-SIPR Pathway as a Potential Therapeutic Approach for COVID-19. International journal of molecular sciences 37 33003377
2022 ALKBH5 Regulates SPHK1-Dependent Endothelial Cell Angiogenesis Following Ischemic Stress. Frontiers in cardiovascular medicine 36 35127873
2005 Activation of the SPHK/S1P signalling pathway is coupled to muscarinic receptor-dependent regulation of peripheral airways. Respiratory research 34 15927078
2016 SPHK1/sphingosine kinase 1-mediated autophagy differs between neurons and SH-SY5Y neuroblastoma cells. Autophagy 33 27467777
2016 Anti-cancer effect of pristimerin by inhibition of HIF-1α involves the SPHK-1 pathway in hypoxic prostate cancer cells. BMC cancer 33 27581969
2010 Sphingosine kinase-1 (SphK-1) regulates Mycobacterium smegmatis infection in macrophages. PloS one 31 20498849
2019 SPHK1-induced autophagy in peritoneal mesothelial cell enhances gastric cancer peritoneal dissemination. Cancer medicine 30 30791228
2019 POTEE drives colorectal cancer development via regulating SPHK1/p65 signaling. Cell death & disease 30 31723122
2017 Crosstalk between TLR2 and Sphk1 in microglia in the cerebral ischemia/reperfusion-induced inflammatory response. International journal of molecular medicine 30 29039449
2015 Activation of SphK1 by K6PC-5 Inhibits Oxygen-Glucose Deprivation/Reoxygenation-Induced Myocardial Cell Death. DNA and cell biology 30 26308910
2022 Diacerein attenuate LPS-induced acute lung injury via inhibiting ER stress and apoptosis: Impact on the crosstalk between SphK1/S1P, TLR4/NFκB/STAT3, and NLRP3/IL-1β signaling pathways. Life sciences 29 36055546
2021 SPHK1 contributes to cisplatin resistance in bladder cancer cells via the NONO/STAT3 axis. International journal of molecular medicine 29 34549307
2021 aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis. Proceedings of the National Academy of Sciences of the United States of America 29 34873055
2021 Blocking SphK1/S1P/S1PR1 Signaling Pathway Alleviates Lung Injury Caused by Sepsis in Acute Ethanol Intoxication Mice. Inflammation 28 34109517
2020 SphK1 promotes development of non‑small cell lung cancer through activation of STAT3. International journal of molecular medicine 28 33236138
2018 Activation of the SphK1/ERK/p-ERK pathway promotes autophagy in colon cancer cells. Oncology letters 27 29928348
2024 Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis. Journal of translational medicine 26 38200582
2020 Relationship between Sphk1/S1P and microRNAs in human cancers. Biotechnology and applied biochemistry 26 32275078
2018 K6PC-5 Activates SphK1-Nrf2 Signaling to Protect Neuronal Cells from Oxygen Glucose Deprivation/Re-Oxygenation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 26 30504702
2016 Overexpression of SphK1 enhances cell proliferation and invasion in triple-negative breast cancer via the PI3K/AKT signaling pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 26 26857281
2023 Trigonelline mitigates bleomycin-induced pulmonary inflammation and fibrosis: Insight into NLRP3 inflammasome and SPHK1/S1P/Hippo signaling modulation. Life sciences 25 37981228
2022 Kaempferol alleviates the inflammatory response and stabilizes the pulmonary vascular endothelial barrier in LPS-induced sepsis through regulating the SphK1/S1P signaling pathway. Chemico-biological interactions 25 36243145
2021 SphK1-driven autophagy potentiates focal adhesion paxillin-mediated metastasis in colorectal cancer. Cancer medicine 25 34268882
2013 Sphingosine kinase (SphK) 1 and SphK2 play equivalent roles in mediating insulin's mitogenic action. Molecular endocrinology (Baltimore, Md.) 25 24422628
2024 Kaempferol mitigates sepsis-induced acute lung injury by modulating the SphK1/S1P/S1PR1/MLC2 signaling pathway to restore the integrity of the pulmonary endothelial cell barrier. Chemico-biological interactions 24 38823539
2023 SPHK1 potentiates colorectal cancer progression and metastasis via regulating autophagy mediated by TRAF6-induced ULK1 ubiquitination. Cancer gene therapy 24 38135696
2019 HJURP Promotes Epithelial-to-Mesenchymal Transition via Upregulating SPHK1 in Hepatocellular Carcinoma. International journal of biological sciences 24 31223275
2019 Sphk1 promotes ulcerative colitis via activating JAK2/STAT3 signaling pathway. Human cell 24 31606874
2018 SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 24 30453304
2016 Sphk1 promotes breast epithelial cell proliferation via NF-κB-p65-mediated cyclin D1 expression. Oncotarget 24 27811358
2022 Pramipexole and Lactoferrin ameliorate Cyclophosphamide-Induced haemorrhagic cystitis via targeting Sphk1/S1P/MAPK, TLR-4/NF-κB, and NLRP3/caspase-1/IL-1β signalling pathways and modulating the Nrf2/HO-1 pathway. International immunopharmacology 23 36194984
2017 Lmo2 (LIM-Domain-Only 2) Modulates Sphk1 (Sphingosine Kinase) and Promotes Endothelial Cell Migration. Arteriosclerosis, thrombosis, and vascular biology 23 28775072
2019 A vaginal nanoformulation of a SphK inhibitor attenuates lipopolysaccharide-induced preterm birth in mice. Nanomedicine (London, England) 22 31793846
2018 Up-regulation and tumor-promoting role of SPHK1 were attenuated by miR-330-3p in gastric cancer. IUBMB life 22 30281914
2022 SphK1 Promotes Cancer Progression through Activating JAK/STAT Pathway and Up-Regulating S1PR1 Expression in Colon Cancer Cells. Anti-cancer agents in medicinal chemistry 20 33797381
2022 The therapeutic effects of cycloastragenol in ulcerative colitis by modulating SphK/MIP-1α/miR-143 signalling. Basic & clinical pharmacology & toxicology 20 36029292
2022 SPHK/HIF-1α Signaling Pathway Has a Critical Role in Chrysin-Induced Anticancer Activity in Hypoxia-Induced PC-3 Cells. Cells 20 36139362
2022 Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer. International journal of molecular sciences 20 36361531
2020 Cell fate determined by the activation balance between PKR and SPHK1. Cell death and differentiation 20 32801355
2024 Targeting SphK1/S1PR3 axis ameliorates sepsis-induced multiple organ injury via orchestration of macrophage polarization and glycolysis. Biochimica et biophysica acta. Molecular cell research 19 39549732
2023 Aralia saponin A isolated from Achyranthes bidentata Bl. ameliorates LPS/D-GalN induced acute liver injury via SPHK1/S1P/S1PR1 pathway in vivo and in vitro. International immunopharmacology 19 37699301
2016 C5a/C5aR pathway is essential for up-regulating SphK1 expression through p38-MAPK activation in acute liver failure. World journal of gastroenterology 19 28028363
2021 LINC00514 promotes lipogenesis and tumor progression in esophageal squamous cell carcinoma by sponging miR‑378a‑5p to enhance SPHK1 expression. International journal of oncology 18 34533201
2025 SPHK1 enhances olaparib resistance in ovarian cancer through the NFκB/NRF2/ferroptosis pathway. Cell death discovery 17 39875359
2023 Baicalin Exerts a Protective Effect in Diabetic Nephropathy by Repressing Inflammation and Oxidative Stress Through the SphK1/S1P/NF-κB Signaling Pathway. Diabetes, metabolic syndrome and obesity : targets and therapy 17 37131503
2023 Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth. Cell death & disease 17 37604912
2022 SphK-produced S1P in somatic cells is indispensable for LH-EGFR signaling-induced mouse oocyte maturation. Cell death & disease 17 36396932
2020 Regulatory role of SphK1 in TLR7/9-dependent type I interferon response and autoimmunity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 31971297
2018 SPHK-2 Promotes the Particle-Induced Inflammation of RAW264.7 by Maintaining Consistent Expression of TNF-α and IL-6. Inflammation 17 29728804
2017 Induction of Sphk1 activity in obese adipose tissue macrophages promotes survival. PloS one 17 28753653
2014 SPHK1 inhibitor suppresses cell proliferation and invasion associated with the inhibition of NF-κB pathway in hepatocellular carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 17 25537088
2022 Fisetin Ameliorates Alcohol-Induced Liver Injury through Regulating SIRT1 and SphK1 Pathway. The American journal of Chinese medicine 16 36266756
2024 SPHK1 promotes bladder cancer metastasis via PD-L2/c-Src/FAK signaling cascade. Cell death & disease 15 39284838
2023 The role of SphK/S1P/S1PR signaling pathway in bone metabolism. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 15 37944444
2021 Deletion or inhibition of SphK1 mitigates fulminant hepatic failure by suppressing TNFα-dependent inflammation and apoptosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 33566377
2024 Triggering of endoplasmic reticulum stress via ATF4-SPHK1 signaling promotes glioblastoma invasion and chemoresistance. Cell death & disease 14 39090107
2024 Sphk1/S1P pathway promotes blood-brain barrier breakdown after intracerebral hemorrhage through inducing Nlrp3-mediated endothelial cell pyroptosis. Cell death & disease 14 39715736
2004 Identification of genetic and epigenetic similarities of SPHK1/Sphk1 in mammals. The Journal of veterinary medical science 14 15585953
2023 Transcriptome and Lipidomic Analysis Suggests Lipid Metabolism Reprogramming and Upregulating SPHK1 Promotes Stemness in Pancreatic Ductal Adenocarcinoma Stem-like Cells. Metabolites 13 37999228
2022 Long non-coding RNA 00960 promoted the aggressiveness of lung adenocarcinoma via the miR-124a/SphK1 axis. Bioengineered 13 34738865
2022 Geniposide inhibits SphK1 membrane targeting to restore macrophage polarization balance in collagen-induced arthritis mice. European journal of pharmacology 13 36108735
2025 Targeting SPHK1 in macrophages remodels the tumor microenvironment and enhances anti-PD-1 immunotherapy efficacy in colorectal cancer liver metastasis. Cancer communications (London, England) 12 40665874
2023 Combined quercetin and simvastatin attenuate hepatic fibrosis in rats by modulating SphK1/NLRP3 pathways. Life sciences 12 38128755
2022 Sphk1-induced autophagy in microglia promotes neuronal injury following cerebral ischaemia-reperfusion. The European journal of neuroscience 12 35766986

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