SNX4 promotes glioblastoma progression through the TGFβ1/Smad signaling pathway and represents a potential therapeutic target
4 affiliations
- 1The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital of Wannan Medical University (Yijishan Hospital of Wannan Medical University), Wuhu, Anhui China
- 2The Institutes of Brain Science, Wannan Medical University, Wuhu, Anhui China
- 3The School of Basic Medical Sciences, Wannan Medical University, Wuhu, Anhui China
- 4Anhui Province Digital Brain Engineering Research Center, Wannan Medical University, Wuhu, Anhui China
Abstract
Background: Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor that still lacks highly specific and clinically effective molecular targets for GBM treatment. Sorting Nexin 4 (SNX4) is an important regulatory molecule involved in intracellular membrane trafficking, protein sorting, and receptor recycling on the cell membrane. However, the roles and mechanism of action of SNX4 in GBM remain unclear.
Methods: RT-qPCR and Western blotting methods were used to measure the expression levels of SNX4 in GBM cell lines and glioma tissue samples from GBM patients. The prognostic role of SNX4 in glioma patients was analyzed by bioinformatic analysis. The roles and underlying mechanism of action of SNX4 in the cell proliferation, cell apoptosis, cell cycle progression, cell migration, and cell invasion of GBM cell lines whose SNX4 gene was silenced or the regulatory pathway of SNX4 was pharmacologically inhibited were examined by the corresponding assays. The role of SNX4 in GBM growth was measured in subcutaneous and intracranial orthotopic tumor models in nude mice. Candidate SNX4-binding small-molecule compounds were discovered by virtual drug screening of a library of small molecule compounds and cell-based drug activity screening.
Results: SNX4 was overexpressed in GBM cell lines and glioma tissue samples from GBM patients measured by RT-qPCR and Western blotting and its high expression was associated with poor prognosis in patients with glioma. SNX4 promoted GBM progression by activating the TGFβ1/Smad signaling pathway in in vitro cell-based assays. Nevertheless, the precise molecular mechanism linking SNX4 to TGFβ receptor trafficking remains to be elucidated. SNX4 also promoted glioma growth in subcutaneous and intracranial orthotopic GBM tumor models in nude mice. Two candidate SNX4-binding small-molecule compounds, G149 and G431, were identified through virtual screening and validated by cell-based assay. Both compounds suppressed GBM growth and were associated with reduced SNX4 expression and inhibition of the TGFβ1/Smad signaling pathway in vitro and in vivo.
Conclusions: Our findings suggest that SNX4 functions as an important regulator of GBM progression, may serve as a potential prognostic biomarker for glioma patients, and may represent a potential therapeutic target.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08784-w.
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BibTeX
@article{yao2026snx4,
title = {{SNX4 promotes glioblastoma progression through the TGFβ1/Smad signaling pathway and represents a potential therapeutic target}},
author = {Zhipeng Yao and Pengcheng Xu and Tianxiao Shen and Yunpeng Hua and Shaodong Ding and Yan Xu and Wenhua Zhong and Xinya Zhao and Shan Jiang and Min Qi and Xiaochun Jiang and Shizhang Ling},
journal = {Journal of Translational Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08784-w},
url = {https://doi.org/10.1186/s12967-026-08784-w},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SNX4 promotes glioblastoma progression through the TGFβ1/Smad signaling pathway and represents a potential therapeutic target
AU - Zhipeng Yao
AU - Pengcheng Xu
AU - Tianxiao Shen
AU - Yunpeng Hua
AU - Shaodong Ding
AU - Yan Xu
AU - Wenhua Zhong
AU - Xinya Zhao
AU - Shan Jiang
AU - Min Qi
AU - Xiaochun Jiang
AU - Shizhang Ling
PY - 2026
DA - 2026/08/11
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-08784-w
UR - https://doi.org/10.1186/s12967-026-08784-w
AB - Background: Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor that still lacks highly specific and clinically effective molecular targets for GBM treatment. Sorting Nexin 4 (SNX4) is an important regulatory molecule involved in intracellular membrane trafficking, protein sorting, and receptor recycling on the cell membrane. However, the roles and mechanism of action of SNX4 in GBM remain unclear. Methods: RT-qPCR and Western blotting methods were used to measure the expression levels of SNX4 in GBM cell lines and glioma tissue samples from GBM patients. The prognostic role of SNX4 in glioma patients was analyzed by bioinformatic analysis. The roles and underlying mechanism of action of SNX4 in the cell proliferation, cell apoptosis, cell cycle progression, cell migration, and cell invasion of GBM cell lines whose SNX4 gene was silenced or the regulatory pathway of SNX4 was pharmacologically inhibited were examined by the corresponding assays. The role of SNX4 in GBM growth was measured in subcutaneous and intracranial orthotopic tumor models in nude mice. Candidate SNX4-binding small-molecule compounds were discovered by virtual drug screening of a library of small molecule compounds and cell-based drug activity screening. Results: SNX4 was overexpressed in GBM cell lines and glioma tissue samples from GBM patients measured by RT-qPCR and Western blotting and its high expression was associated with poor prognosis in patients with glioma. SNX4 promoted GBM progression by activating the TGFβ1/Smad signaling pathway in in vitro cell-based assays. Nevertheless, the precise molecular mechanism linking SNX4 to TGFβ receptor trafficking remains to be elucidated. SNX4 also promoted glioma growth in subcutaneous and intracranial orthotopic GBM tumor models in nude mice. Two candidate SNX4-binding small-molecule compounds, G149 and G431, were identified through virtual screening and validated by cell-based assay. Both compounds suppressed GBM growth and were associated with reduced SNX4 expression and inhibition of the TGFβ1/Smad signaling pathway in vitro and in vivo. Conclusions: Our findings suggest that SNX4 functions as an important regulator of GBM progression, may serve as a potential prognostic biomarker for glioma patients, and may represent a potential therapeutic target. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08784-w.
SN - 1479-5876
ER -