| 2013 |
THBS4 (Thbs4) directly binds Notch1 receptor and promotes its endocytosis, activating downstream Notch signaling (including Nfia transcription factor upregulation) in SVZ neural stem cells to drive astrogenesis over neurogenesis after cortical injury. Thbs4 KO mice show defective injury-induced SVZ astrogenesis, aberrant glial scar formation, and increased microvascular hemorrhage. |
Notch1 receptor binding assay, endocytosis experiments, tamoxifen-inducible lineage tracing (nestin-creERtm4), Thbs4 homozygous knockout mouse phenotyping with cortical photothrombotic injury model |
Nature |
High |
23615612
|
| 2020 |
THBS4 interacts physically with integrin β1 (ITGB1), activating the FAK/PI3K/AKT pathway to promote HCC cell proliferation, metastasis, and EMT progression. |
Co-immunoprecipitation (IP), immunofluorescence, western blot, colony formation assay, transwell assay, xenograft tumor models |
FASEB journal |
Medium |
32567740
|
| 2020 |
PDGFRβ signaling, activated downstream of TGFβ and PDGF-D, promotes post-translational modification of THBS4 from an incomplete to a complete form and drives its secretion via IP3R, STIM1, and Ca2+-signaling proteins, rather than increasing THBS4 mRNA levels. |
IP3R and STIM1 pharmacological blockade, PDGFRβ blockade, western blot for THBS4 protein levels vs. mRNA quantification, conditioned medium functional assays (adhesion, migration, proliferation of CCD-18co cells) |
Cancers |
Medium |
32899998
|
| 2021 |
THBS4, upregulated in BM-MSCs migrating to sites of chronic H. pylori-induced gastric injury, interacts with integrin α2 to activate the PI3K/AKT pathway in endothelial cells, thereby promoting tumor angiogenesis. |
RNA-seq screening, xenograft tumor models, chicken chorioallantoic membrane assay, HUVEC tube formation assay, immunohistochemistry, immunofluorescence |
Aging |
Medium |
34390328
|
| 2024 |
Histone methyltransferase MLL4 acts as a transcriptional activator of Thbs4 via mono-methylation of H3K4 (H3K4me1) and H3K27ac occupancy at the Thbs4 gene locus; MLL4 deficiency markedly reduces THBS4 expression, leading to aggravated ER stress and cardiac dysfunction under pressure overload. |
CUT&Tag-seq, RNA-seq, cardiomyocyte-specific Mll4 knockout mice (pressure overload model), MLL4 knockdown neonatal rat cardiomyocytes, western blot, phenylephrine-induced hypertrophy assay |
Pharmacological research |
High |
38876442
|
| 2025 |
Hypertrophic chondrocyte descendants (PADs) secrete THBS4 to promote angiogenesis; in vitro, exogenous THBS4 alone is sufficient to promote endothelial cell proliferation and tube formation, and rescues defective angiogenesis in HC-ablated metatarsal explants. |
Col10a1-Cre;R26DTA/+ HC genetic ablation mouse model, single-cell RNA-seq, in silico cell-cell communication analysis, immunostaining with tissue clearing, in vitro tube formation assay, metatarsal explant rescue assay |
Bone research |
Medium |
41207902
|
| 2025 |
THBS4 knockdown in HTR-8/SVneo trophoblast cells inhibits TGF-β1 signaling pathway activity and reduces cell proliferation, migration, and invasion; these effects are reversed by TGF-β1 agonist treatment, placing THBS4 upstream of TGF-β1 signaling in trophoblast function. |
siRNA knockdown, TGF-β1 agonist (hyclate) rescue experiment, cell proliferation/migration/invasion assays, western blot |
American journal of physiology. Cell physiology |
Medium |
40478535
|
| 2026 |
Hypoxia induces THBS4 expression via HIF-1α, while TGF-β1 stimulation upregulates THBS4 through SMAD2 and p38 MAPK pathways; elevated THBS4 in turn promotes pulmonary artery smooth muscle cell proliferation, phenotypic modulation, and ECM remodeling in a self-reinforcing THBS4–TGF-β/SMAD2 axis driving pulmonary vascular remodeling. In vivo THBS4 silencing attenuated pulmonary vascular remodeling and right ventricular hypertrophy. |
Whole-transcriptomic analysis of rat PH models, functional assays on pulmonary artery smooth muscle cells, in vivo THBS4 silencing, HIF-1α/SMAD2/p38 MAPK pathway analysis |
Hypertension |
Medium |
41873540
|
| 2025 |
Rehmannin directly binds THBS4 (confirmed by surface plasmon resonance), and THBS4 knockdown enhances while THBS4 overexpression attenuates Rehmannin's inhibitory effects on fibroblast migration, ECM protein expression, and PI3K/AKT pathway activity in the context of pulmonary fibrosis. |
Surface plasmon resonance (SPR) binding assay, siRNA knockdown and overexpression in NIH-3T3 fibroblasts and BMDCs, transcriptomic and metabolomic profiling, in vivo bleomycin fibrosis model |
International immunopharmacology |
Medium |
41202384
|
| 2025 |
THBS4 is localized in the cell membrane and cytoplasm of DRG neurons; overexpression promotes axonal regeneration and reduces neuronal apoptosis, while knockdown has opposite effects. Thbs4 knockdown or overexpression significantly alters NF-κB and ERK signaling pathway activity, implicating these pathways in Thbs4-mediated peripheral nerve repair. |
siRNA knockdown, AAV-mediated overexpression, immunofluorescence staining, behavioral assays, electrophysiological recordings, transmission electron microscopy, sciatic nerve transection rat model |
Biomedicines |
Medium |
41153662
|
| 2020 |
THBS4 silencing in prostate cancer stem cells suppresses self-renewal and proliferation, promotes apoptosis, and reduces in vivo tumorigenicity; PI3K/AKT pathway inhibitor mimics THBS4 silencing effects, and THBS4 overexpression activates the PI3K/AKT pathway, placing THBS4 upstream of PI3K/AKT in cancer stem cell regulation. |
Flow cytometry stem cell sorting, shRNA-mediated THBS4 silencing and overexpression, PI3K/AKT inhibitor treatment, self-renewal/proliferation/apoptosis assays, in vivo tumorigenicity assay, western blot |
The Prostate |
Medium |
32421868
|
| 2026 |
THBS4 enriched in PMSC-derived exosomes binds integrin α2 (ITG α2) on endothelial cells, activating the PI3K/AKT signaling pathway and enhancing endothelial cell migration and angiogenesis; in vivo administration of these exosomes alleviated preeclampsia symptoms in a rat model. |
Exosome isolation and characterization (TEM, nanoparticle tracking, western blot, proteomics), exosome uptake assay, transwell migration assay, tube formation assay, immunofluorescence, rat PE model with intraplacental injection |
International journal of nanomedicine |
Medium |
41878135
|
| 2011 |
THBS4 is expressed and secreted by cancer-associated fibroblasts in diffuse-type gastric adenocarcinoma; tumor cells stimulate THBS4 transcription in fibroblasts. |
Immunohistochemical co-localization, in vitro secretion assays with cancer-associated fibroblasts, tumor cell co-culture experiments, quantitative RT-PCR |
Modern pathology |
Low |
21701537
|
| 2025 |
THBS4 knockdown in renal fibrosis models reduces expression of fibrosis-associated proteins and suppresses PI3K/AKT pathway activation (reduced p-AKT and p-PI3K); these effects are reversed by IGF-1 treatment, placing THBS4 upstream of PI3K/AKT-mediated renal fibrosis. |
UUO mouse model, TGF-β1-stimulated HK2 cell fibrosis model, THBS4 knockdown, IGF-1 rescue, Sirius red/Masson staining, immunohistochemistry, western blot, qPCR |
Frontiers in bioscience |
Medium |
40765330
|
| 2024 |
In a schizophrenia forebrain assembloid model, neuronal PTPRF signaling elicits THBS4 expression in microglia, and this aberrant neuron-glia signaling axis alters the neuronal transcriptome associated with synapse connectivity. |
Patient-derived mix-and-match forebrain assembloids, integrated modular gene expression analysis, combinatorial neuron/glia reconstitution experiments |
bioRxivpreprint |
Low |
|