Affinage

THBS1

Thrombospondin-1 · UniProt P07996

Length
1170 aa
Mass
129.4 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 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

THBS1 (thrombospondin-1) is a secreted matricellular glycoprotein that signals through multiple cell-surface receptors and an intracellular ER stress effector to control angiogenesis, cellular senescence, apoptosis, tissue atrophy, inflammation, and fibrotic remodeling (PMID:34168130, PMID:29042481, PMID:18220792). A recurring theme is THBS1-driven activation of latent TGF-β followed by Smad2/3 signaling, a module exploited across diverse pathologies: skeletal muscle atrophy via a TGFβ-Smad2/3-ATF4 axis coupling autophagy-lysosomal and ubiquitin-proteasome degradation (PMID:38678560), diabetic and septic kidney injury (PMID:35908070, PMID:34756923), blood-brain barrier damage in seizures (PMID:31005663), and tolerogenic dendritic cell generation (PMID:25839231). THBS1 also activates the ER stress kinase PERK to induce ATF4-dependent autophagy and lethal cardiac atrophy, an effect independent of its canonical receptors CD36, CD47, and ATF6α (PMID:34168130). Through CD47, THBS1 drives Nox1-ROS-p53-p21 endothelial senescence (PMID:29042481) and promotes pulmonary vasculopathy via cMyc/ET-1 and ROS pathways (PMID:27742621, PMID:30892078). Its anti-angiogenic activity is mediated by CD36 and resides in the thrombospondin type I repeat (TSR) domain, redirecting pro-angiogenic signaling toward apoptosis (PMID:18220792); a separate von Willebrand type C domain antagonizes BMP-2 and BMP-4 by direct binding (PMID:28747434). THBS1 expression is set by tumor suppressor and oncogenic transcriptional inputs—repression by an ADT-CREB-EZH2 axis (PMID:30287808) and activation by YAP-TEAD to drive FAK-dependent invasion (PMID:30055645). In myeloid cells, THBS1 acts cell-autonomously to promote monocyte adhesion, migration, and matrix invasion (via TIMP1 suppression) during aortic aneurysm formation (PMID:25940549, PMID:33028100).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2005 High

    Established THBS1 as an active mediator rather than a passive matrix marker of tissue injury by showing it directly triggers apoptosis in stressed epithelium.

    Evidence Microarray induction analysis plus purified TSP-1 apoptosis assays (caspase-3, cytochrome c) and TSP-1-null renal ischemia/reperfusion model

    PMID:16294224

    Open questions at the time
    • Receptor mediating the pro-apoptotic signal not defined
    • Downstream apoptotic effector pathway not mapped
  2. 2007 Medium

    Identified CD36 as the endothelial receptor and the TSR domain as the active element for THBS1 anti-angiogenic signaling, defining a structural basis for vascular suppression.

    Evidence Endothelial functional assays and CD36 signaling cascade characterization

    PMID:18220792

    Open questions at the time
    • Abstract-level synthesis without full method detail
    • Molecular link from CD36 to apoptotic conversion incompletely resolved
  3. 2007 Medium

    Linked androgen receptor signaling to THBS1 secretion, showing a hormonal input that tunes tumor angiogenic potential.

    Evidence AR-expressing prostate cancer lines, xenografts, TSP1 ELISA, NFκB reporter assays

    PMID:17487836

    Open questions at the time
    • Whether AR acts directly on THBS1 transcription not established
    • Relative contributions of TSP1 versus NFκB suppression not separated
  4. 2015 High

    Demonstrated cell-autonomous, myeloid-intrinsic THBS1 function driving inflammatory cell infiltration in aneurysm, shifting the model from secreted matrix factor to monocyte-intrinsic effector.

    Evidence Thbs1-/- mice across three AAA models with adoptive transfer and bone marrow reconstitution rescue

    PMID:25940549

    Open questions at the time
    • Receptor mediating monocyte adhesion/migration not identified
    • Downstream signaling in monocytes undefined
  5. 2015 Medium

    Extended the TGF-β-activating role of THBS1 to immune tolerance, showing B cell-derived TSP1 converts latent TGF-β to generate tolerogenic dendritic cells.

    Evidence B cell-deficient mice, methylation-specific PCR, ELISA/flow cytometry

    PMID:25839231

    Open questions at the time
    • Direct demonstration of TSP1-latent TGF-β binding in this context not shown
    • IL-13 methylation mechanism correlative
  6. 2016 High

    Defined a TSP1-CD47-cMyc/ET-1 axis controlling pulmonary vascular tone, mechanistically connecting THBS1 to pulmonary hypertension.

    Evidence CD47-/- mice with hypoxic PH, ex vivo myography, cMyc gain/loss, CD47 blocking antibody in rat monocrotaline model

    PMID:27742621

    Open questions at the time
    • How CD47 engagement regulates cMyc transcriptionally not resolved
    • Endothelial versus smooth muscle contributions not fully separated
  7. 2017 High

    Established a CD47-Nox1-ROS-p53-p21 pathway through which THBS1 drives endothelial senescence and vascular aging.

    Evidence TSP1-/- mice, Nox1 pharmacological inhibition, siRNA, CD47-Nox1 co-IP, aged human lung tissue

    PMID:29042481

    Open questions at the time
    • Direct biochemical coupling of CD47 to Nox1 activation not fully defined
    • Nox1 isoform selectivity mechanism unexplained
  8. 2017 High

    Positioned THBS1 as a downstream effector of KRIT1/KLF2/KLF4 that restrains VEGF signaling and preserves endothelial barrier integrity, linking its loss to cerebral cavernous malformation.

    Evidence Krit1 and Thbs1 mouse genetic models, in vitro TSP1/3TSR reconstitution, 3TSR therapeutic administration

    PMID:28970240

    Open questions at the time
    • Receptor mediating VEGF/tight-junction effects not pinned down
    • Mechanism of KLF-driven THBS1 repression not detailed
  9. 2017 High

    Identified a TGF-β-independent ligand activity of THBS1 as a direct BMP-2/4 antagonist, broadening its growth factor regulatory repertoire and mapping it to the von Willebrand type C domain.

    Evidence Surface plasmon resonance, co-IP, BMP-responsive bioactivity assay in C3H10T1/2 cells

    PMID:28747434

    Open questions at the time
    • Direct domain-deletion proof of the vWC domain requirement not shown
    • Physiological context of BMP antagonism not addressed
  10. 2018 High

    Defined opposing transcriptional control of THBS1 in cancer: EZH2-mediated epigenetic repression enabling angiogenesis versus YAP-TEAD activation driving FAK-dependent invasion.

    Evidence EZH2 ChIP and promoter methylation in ADT prostate models; YAP/TEAD ChIP, luciferase, and siRNA epistasis to pFAK in breast cancer

    PMID:30055645 PMID:30287808

    Open questions at the time
    • How a single gene is anti-angiogenic yet pro-invasive across contexts not reconciled
    • Receptor for FAK activation not identified
  11. 2019 Medium

    Resolved the receptor-proximal events of THBS1-CD47 signaling in distinct vascular beds, showing SHP-2 activation suppressing STAT3-iNOS and ROS-dependent endothelial injury.

    Evidence CD47-SHP-2 co-IP and STAT3/iNOS readouts in retinal cells with CNV model; sickle bone marrow chimeras into CD47KO hosts with ROS assays

    PMID:30892078 PMID:31899207

    Open questions at the time
    • Reciprocal validation of CD47-SHP-2 binding limited
    • How CD47 toggles between ROS-inducing and SHP-2/STAT3-suppressing outputs unclear
  12. 2019 Medium

    Revealed a proteolytic switch in which MT1-MMP cleavage releases a C-terminal THBS1 fragment that engages CD47/αvβ3 to promote NO production and intussusceptive angiogenesis, indicating fragment-specific, context-opposite activities.

    Evidence Endothelial MT1-MMP conditional knockout, intravital microscopy, lentiviral rescue, peptide administration in colitis

    PMID:31793743

    Open questions at the time
    • Cleavage site and fragment identity not biochemically pinned
    • How fragment activity reconciles with full-length anti-angiogenic role unresolved
  13. 2020 High

    Refined the myeloid-intrinsic aneurysm mechanism by showing macrophage THBS1 suppresses TIMP1 to license matrix invasion.

    Evidence Myeloid-specific Thbs1 knockout (Lyz2-cre), RNA FISH, gelatinase assays, Timp1 siRNA rescue

    PMID:33028100

    Open questions at the time
    • Mechanism by which THBS1 represses TIMP1 not defined
    • Whether intracellular or secreted THBS1 mediates the effect unclear
  14. 2021 High

    Identified a receptor-independent intracellular mechanism in which THBS1 binds and activates PERK to drive ATF4-dependent autophagy and lethal cardiac atrophy, distinguishing this from canonical CD36/CD47 signaling.

    Evidence Thbs1 transgenic mice with PERK, ATF6α, CD36, and CD47 knockouts and AAV9 rescue

    PMID:34168130

    Open questions at the time
    • Structural basis of THBS1-PERK binding not solved
    • How a secreted protein accesses the ER lumen to engage PERK not explained
  15. 2024 High

    Generalized the THBS1 atrophy program to skeletal muscle through a TGFβ-Smad2/3-ATF4 axis controlling both autophagy-lysosomal and ubiquitin-proteasome degradation.

    Evidence Muscle-specific Thbs1 transgenics, myofiber TGFβR inhibition, conditional Smad2/3 and Atf4 knockouts, Thbs1-/- denervation/caloric restriction models

    PMID:38678560

    Open questions at the time
    • Relationship between the PERK-ATF4 and TGFβ-Smad2/3-ATF4 routes to ATF4 not reconciled
    • Receptor initiating muscle TGFβ activation not identified
  16. 2025 Medium

    Uncovered a non-matricellular intracellular function whereby exosomal THBS1 binds the deubiquitinase OTUD5 to promote GPX4 ubiquitination and endothelial ferroptosis in cerebral ischemia.

    Evidence THBS1-OTUD5 binding assay, cellular thermal shift, endothelial Gpx4 knockout mice, tMCAO model

    PMID:39994679

    Open questions at the time
    • Mechanism by which THBS1 promotes GPX4 ubiquitination unclear
    • Single lab; reciprocal validation of THBS1-OTUD5 interaction limited

Open questions

Synthesis pass · forward-looking unresolved questions
  • How THBS1 partitions among its mutually exclusive activities—extracellular receptor signaling, latent TGF-β activation, intracellular PERK/OTUD5 engagement, and fragment-specific functions—within a single cell or tissue remains unresolved.
  • No unifying model for how localization and proteolysis dictate which pathway dominates
  • Structural determinants of receptor versus intracellular partner selection unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 4 GO:0048018 receptor ligand activity 3
Localization
GO:0005576 extracellular region 4 GO:0031012 extracellular matrix 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 2
Partners
BMP2BMP4CD36CD47LRRK2OTUD5PERKTLR4

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 THBS1 binds and activates the endoplasmic reticulum stress effector PERK, inducing downstream transcription factor ATF4 and causing lethal autophagy-mediated cardiac atrophy. Deletion of PERK in Thbs1 transgenic mice blunted ATF4 induction and autophagy and largely corrected the lethal cardiac atrophy. Deletion of other THBS1 effectors/receptors (ATF6α, CD36, CD47) did not diminish this effect. Transgenic overexpression, genetic knockout (Thbs1-/-, PERK-/-, ATF6α-/-, CD36-/-, CD47-/-), AAV9 gene transfer, in vivo cardiac phenotyping Nature communications High 34168130
2024 THBS1 activates TGFβ-Smad2/3 signaling in skeletal muscle, which induces ATF4 expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to drive muscle atrophy. Myofiber-specific inhibition of TGFβ-receptor signaling, deletion of Smad2/3, or deletion of Atf4 each antagonized Thbs1-induced muscle atrophy. Thbs1-/- mice showed reduced denervation- and caloric restriction-induced atrophy. Skeletal muscle-specific Thbs1 transgenic mice, myofiber-specific TGFβR inhibition, conditional Smad2/3 knockout, Atf4 knockout, loss-of-function (Thbs1-/-) with denervation/caloric restriction models Cell reports High 38678560
2017 TSP1 promotes endothelial cell senescence through its receptor CD47 by activating NADPH oxidase 1 (Nox1), but not other Nox isoforms, leading to increased ROS, p53 nuclear accumulation, and p21cip upregulation via a DNA damage response. Nox1 inhibition blocked TSP1-induced p53 nuclear localization and senescence. Mice lacking TSP1 showed decreased ROS, p21cip, and aging-induced senescence. TSP1-/- mice, pharmacological Nox1 inhibition, siRNA knockdown, co-immunoprecipitation (CD47-Nox1 axis), human endothelial cell culture, aged human lung tissue analysis Science signaling High 29042481
2017 TSP1 (encoded by Thbs1) is suppressed downstream of KRIT1/KLF2/KLF4 signaling in brain microvascular endothelial cells. Loss of TSP1 enables heightened VEGF signaling and loss of tight junctions. In vitro reconstitution of TSP1 (full-length or the 3TSR anti-angiogenic fragment) suppressed VEGF signaling and preserved tight junctions. Administration of 3TSR prevented cerebral cavernous malformation (CCM) lesion development in Krit1 knockout mice, while inactivation of one or two copies of Thbs1 exacerbated CCM formation. Krit1 mouse knockout, Thbs1 conditional knockout/heterozygous models, in vitro TSP1 reconstitution, 3TSR peptide administration, histology and micro-CT quantification The Journal of experimental medicine High 28970240
2015 TSP1 expressed on monocytic cells (not endothelial or other cells) contributes to their adhesion and migration capacity. Adoptive transfer of wild-type monocytic cells or bone marrow reconstitution rescued aneurysm development in Thbs1-/- mice, demonstrating that monocyte-intrinsic TSP1 drives inflammatory cell infiltration into the aortic wall during AAA development. Thbs1-/- mice, three AAA induction models (CaPO4, elastase, angiotensin II), adoptive transfer of monocytic cells, bone marrow reconstitution, in vitro adhesion/migration assays Circulation research High 25940549
2020 Myeloid/macrophage-derived TSP1 contributes to abdominal aortic aneurysm by suppressing TIMP1 expression, which enables macrophage matrix invasion. Myeloid-specific Thbs1 deletion (Thbs1flox/flox × Lyz2-cre) protected mice from CaCl2-induced AAA. TSP1-deficient macrophages had elevated TIMP1 and reduced gelatinase activity; Timp1 knockdown restored the ability of Thbs1-null macrophages to invade matrix. Myeloid-specific conditional Thbs1 knockout (Lyz2-cre), RNA FISH, gelatinase activity assays, Timp1 siRNA knockdown, in vivo AAA model Arteriosclerosis, thrombosis, and vascular biology High 33028100
2005 TSP-1 is strongly induced in ischemic kidney proximal tubules and causes apoptosis (caspase-3 activation, cytochrome c release) in normal and ATP-depleted proximal tubule cells. TSP-1-null mice were significantly protected from ischemia/reperfusion-induced renal failure and tubular damage, identifying TSP-1 as a mediator of ischemic kidney injury. DNA microarray followed by Northern hybridization, immunocytochemistry (caspase-3, cytochrome c), purified TSP-1 addition to kidney cells in vitro, TSP-1 null mouse IR injury model The Journal of clinical investigation High 16294224
2007 CD36 is an endothelial cell receptor required for TSP-1 and TSP-2 anti-angiogenic activity. CD36-mediated anti-angiogenic signaling redirects pro-angiogenic responses toward apoptosis. The TSP type I repeat (TSR) domain of TSP-1 mediates this activity. Receptor identification studies, endothelial cell functional assays, CD36 signaling cascade characterization (literature synthesis with experimental basis cited) Current pharmaceutical design Medium 18220792
2017 TSP-1 is a BMP-2 and BMP-4 antagonist. Recombinant human TSP-1 binds BMP-2 and BMP-4 as demonstrated by surface plasmon resonance and co-immunoprecipitation, and antagonizes their effects on C3H10T1/2 cells. The von Willebrand type C domain of TSP-1 is implicated in this BMP-2/4-binding activity based on sequence similarity with Crossveinless 2. Surface plasmon resonance, co-immunoprecipitation, BMP-responsive element bioactivity assay in C3H10T1/2 cells, high-resolution mass spectrometry, domain analysis The Journal of biological chemistry High 28747434
2016 TSP1-CD47 signaling promotes pulmonary arterial vasculopathy. In hypoxic wild-type mice, TSP1 and CD47 are upregulated concordantly with ET-1/ETA and downregulation of cMyc. In CD47-/- mice, PH was attenuated, cMyc was overexpressed, and ET-1 was reduced. In CD47+/+ cells, forced cMyc induction suppressed ET-1 transcript; suppression of cMyc increased ET-1 signaling. TSP1 treatment of control pulmonary arteries inhibited vasodilation and potentiated ET-1-mediated vasoconstriction; CD47 blocking antibody improved vasodilator sensitivity in diseased PAs. CD47-/- mice with hypoxia-induced PH, exogenous TSP1 treatment of ex vivo pulmonary arteries, cMyc overexpression/knockdown in CD47+/+ cells, CD47 blocking antibody in rat monocrotaline model, myography Cardiovascular research High 27742621
2019 TSP1 interacts with CD47 to promote pulmonary hypertension in sickle cell disease by increasing reactive oxygen species (ROS) generation in pulmonary endothelial cells. Genetic absence of CD47 in chimeric sickle mice reduced right ventricular pressure, mean pulmonary artery pressure, and pulmonary vascular resistance. TSP1 treatment of human pulmonary artery endothelial cells stimulated ROS generation that was abrogated by CD47 blockade. Bone marrow chimeric mice (BERK sickle marrow into CD47KO hosts), right heart catheterization, ex vivo myography, ROS measurements in human pulmonary endothelial cells with TSP1 treatment and CD47 blockade American journal of physiology. Lung cellular and molecular physiology High 30892078
2018 In prostate cancer, androgen deprivation therapy (ADT) activates CREB, which enhances EZH2 activity. EZH2 directly epigenetically represses THBS1 (TSP1), reducing this anti-angiogenic factor and enabling angiogenesis and neuroendocrine differentiation. Repressing CREB inhibited the CREB/EZH2 axis, tumor growth, neuroendocrine differentiation, and angiogenesis in vivo. In vivo castration/ADT models in xenografts, CREB inhibition, EZH2 ChIP assays, TSP1 promoter methylation analysis, in vivo tumor experiments Nature communications High 30287808
2018 YAP transcriptionally activates THBS1 in a TEAD-dependent manner in breast cancer cells. THBS1 then activates FAK phosphorylation to promote focal adhesion and tumor invasiveness. Silencing THBS1 reversed YAP-induced FAK activation and focal adhesion. Chromatin immunoprecipitation (ChIP), dual luciferase assay, gene expression profiling, Western blot for pFAK, siRNA-mediated THBS1 silencing, transwell invasion assays Journal of experimental & clinical cancer research High 30055645
2013 Lactate induces THBS1 protein expression in glioma cells, and THBS1 in turn activates TGF-β2 (a latent form requiring proteolytic activation). Inhibition of THBS1 by siRNA reduces TGF-β2 protein and glioma cell migration. Addition of synthetic THBS1 rescues reduced TGF-β2 protein levels and glioma cell migration in LDH-A knockdown (low-lactate) cells. siRNA knockdown of LDH-A and THBS1, lactate addition/rescue experiments, Western blot, ELISA, spheroid/scratch/Boyden chamber migration assays PloS one Medium 24223867
2020 Intermittent hypoxia (IH) induces TSP1 expression in cardiac fibroblasts through STAT3 phosphorylation at Tyr705. TSP1 upregulation mediates IH-induced cardiac fibroblast activation and cardiac fibrosis. STAT3 inhibition (pharmacological S3I-201 or AAV9-shStat3 in cardiac fibroblasts) significantly attenuated synergistic cardiac fibrosis from IH and angiotensin II. IH mouse model, in vitro cardiac fibroblast culture, STAT3 pharmacological inhibition and AAV9-driven shRNA knockdown, plasma TSP1 ELISA in OSA patients eLife Medium 31934850
2007 Androgen receptor (AR) expression increases TSP1 secretion by prostate cancer cells, decreasing their angiogenic potential. AR activation also decreases RelA (NFκB subunit) nuclear localization and transcriptional activity, reducing Bcl-2 and IL-6 expression. Combined NFκB suppression and increased TSP1 underlie AR anti-tumor activity in vivo. Stable AR-expressing prostate cancer cell lines, tumor xenografts in male mice, ELISA for TSP1 secretion, immunostaining for vascularity/apoptosis, NFκB reporter assays International journal of cancer Medium 17487836
2015 B cell-derived TSP1 converts latent TGF-β to active TGF-β in dendritic cells, generating TGF-β-producing tolerogenic dendritic cells (TolDCs). IL-13 inhibits TSP1 expression in B cells by enhancing TSP1 gene DNA methylation, thereby impairing TolDC generation. B cell-deficient mouse model (anti-CD20 antibody), flow cytometry, ELISA, qRT-PCR, Western blot, methylation-specific PCR The Journal of biological chemistry Medium 25839231
2019 TSP1 activates SHP-2 through its receptor CD47, reducing STAT3 phosphorylation and thereby blocking the STAT3-iNOS pathway and reducing nitric oxide concentration in retinal endothelial cells. This mechanism protects against choroidal neovascularization (CNV) in age-related macular degeneration. Co-immunoprecipitation showed CD47-SHP-2 binding in response to TSP1. Co-immunoprecipitation (CD47-SHP-2), TSP1 overexpression in RF/6A cells, CCK-8 viability, flow cytometry (apoptosis), transwell migration, Western blot for STAT3/iNOS, CNV mouse model Experimental cell research Medium 31899207
2019 Senescent cells produce TSP1, which prevents senescence escape in breast cancer cells. Senescence escape is mediated by CD47low cells that arise when p21waf1 is downregulated, enabling Myc upregulation, which binds the CD47 promoter to repress CD47 expression, allowing cells to escape TSP1-mediated suppression. SWATH quantitative proteomic analysis, in vitro and in vivo senescence models, ChIP (Myc binding to CD47 promoter), p21 siRNA-mediated downregulation, serum TSP1 measurement in breast cancer patients Cell death & disease Medium 30814491
2019 TSP1 promotes follicular angiogenesis, luteinization, and ovulation in primates. THBS1 treatment of monkey ovarian microvascular endothelial cells stimulated migration, proliferation, and capillary sprout formation in vitro. Intra-follicular injection of anti-THBS1 antibody reduced follicle rupture, oocyte release, granulosa cell layer expansion, endothelial cell invasion, and capillary formation. In vitro endothelial cell migration/proliferation/tube formation assays, intra-follicular anti-THBS1 antibody injection in cynomolgus macaques, follicle histology Frontiers in endocrinology Medium 31787928
2025 THBS1 in macrophage-derived exosomes binds directly to OTUD5 and promotes GPX4 ubiquitination, leading to ferroptosis in endothelial cells during cerebral ischemia-reperfusion injury. Modulation of THBS1 in macrophage-derived exosomes affected endothelial ferroptosis. Salvianolic acid B inhibited the THBS1-OTUD5 interaction, reducing GPX4 ubiquitination and protecting against CIRI. RNA interference, AAV transfection, endothelial-specific Gpx4 knockout mice, proteomic sequencing, THBS1-OTUD5 binding assay, cellular thermal shift assay, molecular docking/MD simulation, tMCAO mouse model Journal of neuroinflammation Medium 39994679
2023 THBS1 from bone marrow-derived monocyte-like cells (recruited by CXCL12) contributes to colorectal cancer metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. THBS1 loss in the tumor microenvironment rendered tumors partially sensitive to immune checkpoint inhibitors. Orthotopic CRC mouse models, THBS1 knockout in TME, immune cell profiling, tumor growth and metastasis assays, immune checkpoint inhibitor combination experiments Nature communications Medium 37749092
2019 P2Y4 receptor activation regulates TSP-1 expression, which activates TGF-β1/pSmad2/3 signaling to promote angiogenesis and blood-brain barrier damage during acute seizures. Inhibition of TSP-1 by siRNA or LSKL peptide (TGF-β1 activation inhibitor) prevented KA-induced Smad2/3 phosphorylation, angiogenesis, BBB damage, and acute seizures. siRNA-mediated TSP-1 knockdown, LSKL peptide inhibition, P2 receptor antagonists, kainic acid seizure model in rats, immunostaining and Western blot Brain research bulletin Medium 31005663
2022 Sestrin2 overexpression modulates the activity of the TSP-1/TGF-β1/Smad3 pathway in podocytes under high glucose conditions. TSP-1 inhibition by LSKL peptide or TGF-β1 blockade arrested high-glucose-induced podocyte injury, placing TSP-1 upstream of TGF-β1 activation in diabetic kidney disease. Sestrin2 transgenic mice, STZ-induced diabetes model, podocyte cell culture, LSKL peptide inhibition, Pirfenidone (TGF-β blocker), pathway protein analysis by Western blot Cell death & disease Medium 35908070
2023 LRRK2 G2019S mutation promotes ER stress in neurons by directly interacting with THBS1, which in turn interacts with TGF-β1. Knocking down THBS1 rescued ER stress and behavioral burden caused by the LRRK2 mutation. Suppression of TGF-β1 had a similar effect, placing THBS1 between LRRK2 G2019S and TGF-β1 in ER stress signaling. iPSC-derived dopamine neurons, LRRK2 G2019S mouse model, co-immunoprecipitation (LRRK2-THBS1 interaction), THBS1 and TGF-β1 knockdown, LRRK2 kinase inhibition Advanced science Medium 37672887
2021 USF2 transcriptionally activates THBS1 to activate the TGF-β/Smad3/NLRP3/Caspase-1 signaling pathway, promoting pyroptosis in sepsis-induced acute kidney injury. USF2 knockdown downregulated THBS1 and inhibited the TGF-β/Smad3 pathway and pyroptosis. USF2 and THBS1 siRNA knockdown, sepsis AKI mouse model, in vitro cell model, qRT-PCR, ELISA, Western blot for NLRP3/Caspase-1/GSDMD pathway components Pharmacological research Medium 34756923
2013 PRMT6 overexpression strongly upregulates TSP-1 expression in MCF7 and PC3 cancer cells. Specific knockdown of TSP-1 significantly rescued the suppression of migration and invasion caused by PRMT6 overexpression, placing TSP-1 downstream of PRMT6 in the regulation of cancer cell motility. Stable PRMT6-overexpressing cell lines, siRNA knockdown of TSP-1, cell migration/invasion assays, Western blot Biochemical and biophysical research communications Low 23380452
2019 In endothelial cells, MT1-MMP cleaves TSP1, and the C-terminal fragment of TSP1 binds CD47/αvβ3 integrin to promote nitric oxide production required for vasodilation and intussusceptive angiogenesis. MT1-MMP deletion in endothelial cells limited IA and reduced NO production; lentiviral rescue experiments confirmed requirement for MT1-MMP activity. MT1-MMP endothelial conditional knockout mice, intravital microscopy, lentiviral rescue, in vitro cell culture, anti-MT1-MMP antibody and αvβ3-binding TSP1 peptide administration in colitis model EMBO molecular medicine Medium 31793743
2021 TSP1 promotes keloid fibroblast proliferation and collagen I deposition through the IL6/JAK2/STAT3 signaling pathway. Knockdown of TSP1 decreased proliferation and collagen I; exogenous TSP1 treatment increased both in normal fibroblasts. TSP1 expression positively correlated with IL6/STAT3 signaling activity in keloid tissues. siRNA knockdown of TSP1 in keloid fibroblasts, exogenous TSP1 treatment of normal fibroblasts, Western blot and immunohistochemistry, IL6/JAK2/STAT3 pathway analysis Experimental dermatology Low 35661430
2022 Inhibiting THBS1 expression in ECFC-derived exosomes activates PI3K, AKT, and ERK phosphorylation in endothelial cells, promoting VEGF and bFGF expression and enhancing angiogenesis and bone formation in distraction osteogenesis. Lentiviral THBS1 knockdown in ECFCs, exosome isolation and application to HUVECs, Western blot for PI3K/AKT/ERK, tube formation/migration/proliferation assays, in vivo canine mandibular DO model with peripheral blood exosome injection Journal of orthopaedic translation Low 36196150
2025 Under normoxic conditions, TGFβ1 inhibits angiogenesis by upregulating TSP1 in endothelial cells via TGFβR1-SMAD2/3 signaling. In hypoxia, HIF1α induces miR-145, which represses SMAD2/3 and subsequently reduces TSP1 levels in endothelial cells, thereby abrogating the anti-angiogenic effect of TGFβ1. Chick chorioallantoic membrane assays, zebrafish angiogenesis models, mouse hepatoma xenografts, HIF1α inhibitor/stabilizer treatments, miR-145 overexpression, SMAD2/3 knockdown, TSP1 measurement in endothelial cells and human HCC specimens Cancer research Medium 39356626
2022 m6A reader IGF2BP1 binds and stabilizes THBS1 mRNA in an m6A-dependent manner in macrophages, promoting macrophage M2 polarization and glycolytic reprogramming. THBS1 physically interacts with TLR4 to mediate these downstream effects. TLR4 overexpression reversed the inhibitory effect of THBS1 knockdown on M2 polarization and glycolysis. IGF2BP1 knockdown in BLM-induced PF mice, RIP (RNA immunoprecipitation) for THBS1 mRNA, co-immunoprecipitation (THBS1-TLR4), THBS1 overexpression rescue, glycolysis assays, M2 polarization flow cytometry Cellular and molecular life sciences Medium 40220148
2022 Cell surface GRP78 (csGRP78) regulates high-glucose-induced TSP1 transcriptional upregulation via PI3K/Akt signaling in glomerular mesangial cells, enabling TSP1-dependent TGF-β1 activation and downstream Smad3 signaling. Inhibition of csGRP78 prevented HG-induced TSP1 upregulation and TGF-β1 activation. csGRP78 inhibitors (vaspin, C38 antibody, MTJ-1 siRNA, α2M* neutralization), TSP1 promoter assays, Smad3 activation assays, PI3K/Akt inhibitors, primary mouse mesangial cells Frontiers in pharmacology Medium 36909183
2021 Platelet TSP-1 controls prostate cancer-induced osteoclast differentiation and bone marrow-derived cell (BMDC) mobilization through TGF-β1. TSP-1 deletion in tumor-bearing mice reduced BMDC mobilization and increased osteoclast formation. Platelet-specific TGF-β1 deletion (PF4-cre) phenocopied TSP-1 deletion effects on osteoclastogenesis and bone formation, placing TSP-1 upstream of TGF-β1 release from platelets. TSP-1 null mice with RM1 tumor implantation, platelet-specific TGF-β1 deletion (PF4-cre), microcomputed tomography, immunohistochemistry, bone marrow cell mobilization assay American journal of clinical and experimental urology Medium 33816691
2015 TSP1 and its receptors CD36 and CD47 are upregulated in sporadic inclusion body myositis muscle. TNF-α upregulates TSP1 and CD47 production by myoblasts in vitro, suggesting TNF-α drives TSP1-CD36/CD47 complex formation in chronic muscle inflammation. mRNA and protein expression analysis in IBM muscle biopsies, immunolocalization, cytokine stimulation (TNF-α) of human myoblasts in vitro Journal of neuroimmunology Low 17572512
2015 TSP1 loss in mice lacking TSP1 is associated with decreased expression of voltage-dependent calcium channel subunit CACNA2D2 mRNA and α2δ-1/2 protein in the cortex, correlating with increased seizure susceptibility in PTZ kindling. TSP2 knockout did not affect kindling, placing TSP1 specifically in the regulation of CACNA2D2 levels and seizure threshold. TSP1-/-, TSP2-/-, and double TSP1/2-/- mice, PTZ kindling model, qRT-PCR for CACNA2D2 and CACNA2D1, Western blot for α2δ-1/2 protein Neuroscience Low 26241338

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice. The American journal of pathology 260 12213711
2011 MicroRNA-18 and microRNA-19 regulate CTGF and TSP-1 expression in age-related heart failure. Aging cell 215 21501375
2018 Hippo component YAP promotes focal adhesion and tumour aggressiveness via transcriptionally activating THBS1/FAK signalling in breast cancer. Journal of experimental & clinical cancer research : CR 186 30055645
2018 Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers. Nature communications 178 30287808
1993 Expression of thrombospondin (TSP1) and its receptors (CD36 and CD51) in normal, hyperplastic, and neoplastic human breast. Cancer research 142 7680285
2021 Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy. Nature communications 137 34168130
2021 USF2 knockdown downregulates THBS1 to inhibit the TGF-β signaling pathway and reduce pyroptosis in sepsis-induced acute kidney injury. Pharmacological research 123 34756923
2015 Thrombospondin-1 (TSP1) contributes to the development of vascular inflammation by regulating monocytic cell motility in mouse models of abdominal aortic aneurysm. Circulation research 111 25940549
2005 Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia. The Journal of clinical investigation 109 16294224
1996 Thrombospondin-1 (TSP-1) promotes the invasive properties of human breast cancer. The Journal of surgical research 89 8661169
2020 THBS1 (thrombospondin-1). Atlas of genetics and cytogenetics in oncology and haematology 87 33244322
2017 Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations. The Journal of experimental medicine 84 28970240
2017 The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Science signaling 83 29042481
2023 THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer. Nature communications 80 37749092
2019 HDAC6 Suppresses Let-7i-5p to Elicit TSP1/CD47-Mediated Anti-Tumorigenesis and Phagocytosis of Hepatocellular Carcinoma. Hepatology (Baltimore, Md.) 75 30991448
2019 Regulation of senescence escape by TSP1 and CD47 following chemotherapy treatment. Cell death & disease 72 30814491
2013 Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro. PloS one 72 24223867
2016 TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction. Cardiovascular research 71 27742621
2017 Role of HTLV-1 Tax and HBZ in the Pathogenesis of HAM/TSP. Frontiers in microbiology 67 29312243
2020 THBS1 facilitates colorectal liver metastasis through enhancing epithelial-mesenchymal transition. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 57 32052380
2010 Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors. Oncotarget 55 21317461
2012 Thrombospondin-1 (TSP1)-null and TSP2-null mice exhibit lower intraocular pressures. Investigative ophthalmology & visual science 53 22930728
2019 Thrombospondin 1 (THBS1) Promotes Follicular Angiogenesis, Luteinization, and Ovulation in Primates. Frontiers in endocrinology 51 31787928
2008 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) inflammatory network. Inflammation & allergy drug targets 49 18691139
2007 Androgen receptor targets NFkappaB and TSP1 to suppress prostate tumor growth in vivo. International journal of cancer 49 17487836
2022 Sestrin2 remedies podocyte injury via orchestrating TSP-1/TGF-β1/Smad3 axis in diabetic kidney disease. Cell death & disease 45 35908070
2020 Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis. eLife 45 31934850
2014 Antiangiogenic variant of TSP-1 targets tumor cells in glioblastomas. Molecular therapy : the journal of the American Society of Gene Therapy 44 25358253
2004 Role of TSP-5/COMP in pseudoachondroplasia. The international journal of biochemistry & cell biology 44 15094116
2014 Immunopathogenesis of HTLV-1-assoaciated myelopathy/tropical spastic paraparesis (HAM/TSP). Life sciences 43 24704970
2021 COMP and TSP-4: Functional Roles in Articular Cartilage and Relevance in Osteoarthritis. International journal of molecular sciences 42 33668140
2019 Vascular TSP1-CD47 signaling promotes sickle cell-associated arterial vasculopathy and pulmonary hypertension in mice. American journal of physiology. Lung cellular and molecular physiology 42 30892078
2020 Myeloid-Derived TSP1 (Thrombospondin-1) Contributes to Abdominal Aortic Aneurysm Through Suppressing Tissue Inhibitor of Metalloproteinases-1. Arteriosclerosis, thrombosis, and vascular biology 41 33028100
2020 TSP-1 (Thrombospondin-1) Deficiency Protects ApoE-/- Mice Against Leptin-Induced Atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 40 33327743
2003 Reduced expression of the TSP1 gene and its association with promoter hypermethylation in gastric carcinoma. Oncology 40 12759541
2023 LRRK2 Gly2019Ser Mutation Promotes ER Stress via Interacting with THBS1/TGF-β1 in Parkinson's Disease. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 39 37672887
2019 Endothelial MT1-MMP targeting limits intussusceptive angiogenesis and colitis via TSP1/nitric oxide axis. EMBO molecular medicine 37 31793743
2007 CD36-TSP-HRGP interactions in the regulation of angiogenesis. Current pharmaceutical design 34 18220792
2013 The role of thrombospondin (TSP)-1 in obesity and diabetes. Adipocyte 33 24575376
2024 Thbs1 regulates skeletal muscle mass in a TGFβ-Smad2/3-ATF4-dependent manner. Cell reports 32 38678560
2008 Model systems for studying skeletal dysplasias caused by TSP-5/COMP mutations. Cellular and molecular life sciences : CMLS 32 18193163
2024 Oxidative stress promotes oral carcinogenesis via Thbs1-mediated M1-like tumor-associated macrophages polarization. Redox biology 29 39255693
2022 ECFC-derived exosomal THBS1 mediates angiogenesis and osteogenesis in distraction osteogenesis via the PI3K/AKT/ERK pathway. Journal of orthopaedic translation 28 36196150
2020 The circular RNA aplacirc_13267 upregulates duck granulosa cell apoptosis by the apla-miR-1-13/THBS1 signaling pathway. Journal of cellular physiology 28 31970783
2013 PRMT6 overexpression upregulates TSP-1 and downregulates MMPs: its implication in motility and invasion. Biochemical and biophysical research communications 26 23380452
2025 THBS1 in macrophage-derived exosomes exacerbates cerebral ischemia-reperfusion injury by inducing ferroptosis in endothelial cells. Journal of neuroinflammation 25 39994679
2015 Thrombospondin-1 (TSP1)-producing B cells restore antigen (Ag)-specific immune tolerance in an allergic environment. The Journal of biological chemistry 25 25839231
2020 TSP1-CD47-SIRPα signaling facilitates the development of endometriosis by mediating the survival of ectopic endometrium. American journal of reproductive immunology (New York, N.Y. : 1989) 24 32196807
2010 ADAMTS1 alters blood vessel morphology and TSP1 levels in LNCaP and LNCaP-19 prostate tumors. BMC cancer 23 20546609
2023 The long noncoding RNA THBS1-AS1 promotes cardiac fibroblast activation in cardiac fibrosis by regulating TGFBR1. JCI insight 22 36787190
2022 Sphingomyelin nanosystems decorated with TSP-1 derived peptide targeting senescent cells. International journal of pharmaceutics 22 35219823
2022 Single-cell RNA sequencing identifies a migratory keratinocyte subpopulation expressing THBS1 in epidermal wound healing. iScience 22 35391830
2021 Targeting Ovarian Carcinoma with TSP-1:CD47 Antagonist TAX2 Activates Anti-Tumor Immunity. Cancers 22 34638503
2023 Tsp-1+ microglia attenuate retinal neovascularization by maintaining the expression of Smad3 in endothelial cells through exosomes with decreased miR-27a-5p. Theranostics 21 37441592
2022 TSP1 promotes fibroblast proliferation and extracellular matrix deposition via the IL6/JAK2/STAT3 signalling pathway in keloids. Experimental dermatology 21 35661430
2023 LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1. Nature communications 20 36899005
2007 Upregulation of thrombospondin-1(TSP-1) and its binding partners, CD36 and CD47, in sporadic inclusion body myositis. Journal of neuroimmunology 20 17572512
2024 Nattokinase attenuates endothelial inflammation through the activation of SRF and THBS1. International journal of biological macromolecules 19 38679250
2021 TSP1 is the essential domain of SEMA5A involved in pannus formation in rheumatoid arthritis. Rheumatology (Oxford, England) 19 33616619
2021 MYC-mediated upregulation of PNO1 promotes glioma tumorigenesis by activating THBS1/FAK/Akt signaling. Cell death & disease 19 33664245
2019 P2Y4/TSP-1/TGF-β1/pSmad2/3 pathway contributes to acute generalized seizures induced by kainic acid. Brain research bulletin 19 31005663
2024 THBS1 and THBS2 Enhance the In Vitro Proliferation, Adhesion, Migration and Invasion of Intrahepatic Cholangiocarcinoma Cells. International journal of molecular sciences 18 38339060
2014 HTLV-1 proviral integration sites differ between asymptomatic carriers and patients with HAM/TSP. Virology journal 18 25270762
2024 The role of SPI1/VSIG4/THBS1 on glioblastoma progression through modulation of the PI3K/AKT pathway. Journal of advanced research 17 38960279
2021 Platelet TSP-1 controls prostate cancer-induced osteoclast differentiation and bone marrow-derived cell mobilization through TGFβ-1. American journal of clinical and experimental urology 17 33816691
2021 Curcumin improves angiogenesis in the heart of aged rats: Involvement of TSP1/NF-κB/VEGF-A signaling. Microvascular research 17 34543634
2019 Association Between HTLV-1 Genotypes and Risk of HAM/TSP. Frontiers in microbiology 17 31156605
2014 Common and rare variants of the THBS1 gene associated with the risk for autism. Psychiatric genetics 17 25304225
2022 PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression. Nature communications 16 36575174
2020 miR-205 inhibits the development of hypertrophic scars by targeting THBS1. Aging 16 33186919
2019 TSP1 ameliorates age-related macular degeneration by regulating the STAT3-iNOS signaling pathway. Experimental cell research 16 31899207
2009 NF-kappaB blockade upregulates Bax, TSP-1, and TSP-2 expression in rat granulation tissue. Journal of molecular medicine (Berlin, Germany) 16 19189070
2025 HIF1α Counteracts TGFβ1-Driven TSP1 Expression in Endothelial Cells to Stimulate Angiogenesis in the Hypoxic Tumor Microenvironment. Cancer research 15 39356626
2023 The Periplasmic Tail-Specific Protease, Tsp, Is Essential for Secondary Differentiation in Chlamydia trachomatis. Journal of bacteriology 15 37092988
2019 TSP-1 is downregulated and inversely correlates with miR-449c expression in Cushing's disease. Journal of cellular and molecular medicine 15 31016850
2024 Activation of SIRT3 by Tanshinone IIA ameliorates renal fibrosis by suppressing the TGF-β/TSP-1 pathway and attenuating oxidative stress. Cellular signalling 14 39153586
2023 Roles of TSP1-CD47 signaling pathway in senescence of endothelial cells: cell cycle, inflammation and metabolism. Molecular biology reports 14 36897523
2016 Analyses of HTLV-1 sequences suggest interaction between ORF-I mutations and HAM/TSP outcome. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 14 27553711
2021 Clinical trial of raltegravir, an integrase inhibitor, in HAM/TSP. Annals of clinical and translational neurology 13 34562313
2024 The CD47/TSP-1 axis: a promising avenue for ovarian cancer treatment and biomarker research. Molecular cancer 12 39138571
2023 Conservation, abundance, glycosylation profile, and localization of the TSP protein family in Cryptosporidium parvum. The Journal of biological chemistry 12 36775128
2023 Cell surface GRP78 regulates TGFβ1-mediated profibrotic responses via TSP1 in diabetic kidney disease. Frontiers in pharmacology 12 36909183
2023 Enterolactone and trabectedin suppress epithelial ovarian cancer synergistically via upregulating THBS1. Phytotherapy research : PTR 12 37443453
2021 Targeting TSP-1 decreased periodontitis by attenuating extracellular matrix degradation and alveolar bone destruction. International immunopharmacology 12 34015597
2021 miR-1290 contributes to oncogenesis and angiogenesis via targeting of THBS1, DKK3 and, SCAI. BioImpacts : BI 12 35975203
2016 New Markers in Atherosclerosis: Thrombospondin-2 (THBS-2) and Leukocyte Cell-Derived Chemotaxin-2 (LECT-2); An Immunohistochemical Study. Medical science monitor : international medical journal of experimental and clinical research 12 28039493
2024 TSP-1 increases autophagy level in cartilage by upregulating HSP27 which delays progression of osteoarthritis. International immunopharmacology 11 38183909
2024 THBS1 promotes angiogenesis and accelerates ESCC malignant progression by the HIF-1/VEGF signaling pathway. Cell biology international 11 38233982
2017 Thrombospondin-1 (TSP-1), a new bone morphogenetic protein-2 and -4 (BMP-2/4) antagonist identified in pituitary cells. The Journal of biological chemistry 11 28747434
2017 ADAMTS1-mediated targeting of TSP-1 by PPARδ suppresses migration and invasion of breast cancer cells. Oncotarget 11 29212212
2009 Gene activation therapy: from the BLV model to HAM/TSP patients. Frontiers in bioscience (Scholar edition) 11 19482696
1994 Expression of thrombospondin-1 (TSP1) and its receptor (CD36) in healthy and diseased human skin. Acta dermato-venereologica 11 7526582
2025 m6A reader IGF2BP1 facilitates macrophage glycolytic metabolism and fibrotic phenotype by stabilizing THBS1 mRNA to promote pulmonary fibrosis. Cellular and molecular life sciences : CMLS 10 40220148
2024 The long noncoding RNA lncMPD2 inhibits myogenesis by targeting the miR-34a-5p/THBS1 axis. International journal of biological macromolecules 10 38971281
2022 Levofloxacin exerts broad-spectrum anticancer activity via regulation of THBS1, LAPTM5, SRD5A3, MFAP5 and P4HA1. Anti-cancer drugs 10 34419964
2022 The TSP-1 domain of the matricellular protein CCN5 is essential for its nuclear localization and anti-fibrotic function. PloS one 10 35476850
2021 Comparative Cytotoxicity Study of PM2.5 and TSP Collected from Urban Areas. Toxics 10 34357910
2015 Increased sensitivity to kindling in mice lacking TSP1. Neuroscience 10 26241338
2023 MicroRNA-221-3p Targets THBS1 to Promote Wound Healing in Diabetes. Diabetes, metabolic syndrome and obesity : targets and therapy 9 37720423
2015 T cell receptor signaling pathway is overexpressed in CD4(+) T cells from HAM/TSP individuals. The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases 9 26358743

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