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Role of matrix metalloproteinases in the invasion of glioblastoma and drug interventions (Review)

  • Authors:
    • Bohao Zheng
    • Ying Han
    • Haiying Zhang
  • View Affiliations / Copyright

    Affiliations: The First Clinical College of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110000, P.R. China, The First Clinical College of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110000, P.R. China
    Copyright: © Zheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 33
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    Published online on: December 1, 2025
       https://doi.org/10.3892/ijmm.2025.5704
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Abstract

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor type in adults, and is characterized by high invasiveness, therapeutic resistance and recurrence. Current treatments, primarily surgery combined with radiotherapy and chemotherapy, offer limited efficacy, thus necessitating more effective interventions. Matrix metalloproteinases (MMPs) crucially contribute to GBM progression through extracellular matrix degradation, epithelial‑mesenchymal transition and angiogenesis. MMP expression is intricately regulated by signaling pathways, non‑coding RNAs and the tumor microenvironment. Recently, strategies targeting MMPs have gained attention, including natural active substances and small‑molecule compounds with promising therapeutic potential. Nano‑delivery systems have notably improved drug delivery efficiency to the brain by overcoming the blood‑brain barrier, and combination therapies have demonstrated enhanced efficacy. However, chemotherapy resistance and functional heterogeneity remain critical challenges. The present review summarizes recent advances in understanding MMP regulatory mechanisms in GBM, highlighting the roles of signaling pathways and non‑coding RNAs. Additionally, the therapeutic potential of natural products, small‑molecule inhibitors, smart nanocarriers and combination treatments are discussed. Future research should focus on identifying novel inhibitors, and leveraging interdisciplinary approaches to facilitate precision‑targeted drug development, thereby addressing current treatment bottlenecks in GBM.
View Figures

Figure 1

ECM in normal brain tissue vs. GBM.
In normal state, the brain ECM is primarily composed of and
maintained by brain microvascular endothelial cells, astrocytes,
microglia, oligodendrocytes, neurons and the surrounding
perineuronal nets. Components such as collagen and proteoglycans
are interwoven within this structure, ensuring the structural and
functional stability of the neurovascular unit. In GBM pathological
state, MMPs accumulate in the BBB region, degrading the
perivascular basement membrane, astrocytic end-feet structures and
key ECM components such as collagen and proteoglycans, thereby
disrupting ECM homeostasis and leading to BBB leakage. EVs released
by GBM cells can induce astrocytes to secrete MMPs; these EVs are
also taken up by neighboring GBM cells, promoting an invasive
phenotype. EVs released by endothelial cells can induce
epithelial-mesenchymal transition in GBM stem cells. Furthermore,
MMPs released by neutrophils promote tumor angiogenesis by
modulating the expression of angiogenesis-related factors,
collectively driving GBM invasion. → indicates the direction of
action; key factors contained within EVs are indicated in
parentheses. ECM, extracellular matrix; GBM, glioblastoma; MMP,
matrix metalloproteinase; BBB, blood-brain barrier; EVs,
extracellular vesicles; EMT, epithelial-mesenchymal transition;
GSCs, glioma stem cells; sEVs, small extracellular vesicles; EEVs,
endothelial cell-derived extracellular vesicles. Created in
BioRender. Zheng, B. (2025) https://BioRender.com/dxwgq2l.

Figure 2

Key signaling pathway networks
regulating matrix MMPs. The PI3K/AKT/mTOR, Wnt/β-catenin, MAPK,
TGF-β and Hippo signaling pathways constitute the core network
regulating the expression and activity of MMPs. Additionally, key
signaling molecules such as FAK and Src are involved. Effector
proteins such as GIGYF2 and TOP2A primarily influence MMPs by
regulating AKT and β-catenin signaling. By contrast, FABP6 and
PPFIBP1 indirectly modulate MMP activity by acting on multiple
signaling pathways. → indicates promotion; --- indicates an
inferred interaction based on literature evidence that has not been
directly reported; ⊥ indicates inhibition. MMP, metalloproteinase.
Created in BioRender. Zheng, B. (2025) https://BioRender.com/dxwgq2l.

Figure 3

Mechanisms of non-coding RNA
regulation of MMPs. Circular RNA primarily functions as a ceRNA,
influencing the expression and function of MMPs by sponging miRNAs.
Additionally, ubiquitination modifications and related kinases are
involved in mediating miRNA-mediated regulation of MMPs.
Furthermore, miRNAs can also affect MMPs by modulating the activity
of the PI3K/AKT signaling pathway in the cytoplasm. → indicates
promotion; ⊥ indicates inhibition; a denotes ceRNA function; b
denotes the ubiquitination process. MMP, matrix metalloproteinase;
ceRNA, competing endogenous RNA; miRNA or miR, microRNA. Created in
BioRender. Zheng, B. (2025) https://BioRender.com/dxwgq2l.

Figure 4

Mechanisms of MMP regulation in the
TME. The expression of MMPs is regulated by metabolic reprogramming
(lipid metabolism), physical factors (osmotic/hydrostatic pressure
and static magnetic fields) and hypoxic conditions within the TME.
Cell membrane-associated structures (caveolae), membrane proteins
(AQP1 and TLR2) and membrane-type MMPs also participate in the
regulation of MMP expression and activity. At the immune cell
level, M1 macrophages, neutrophils and myeloid-derived suppressor
cells significantly influence MMP expression levels. Notably, MMP
levels in M2 macrophages and glioblastoma stem cells are regulated
by specific proteins (RGS4 and ALDH1A2). → indicates
promotion/stimulation; --- indicates an inferred interaction based
on literature evidence but not directly reported; ⊥ indicates
inhibition/suppression; a indicates M1 macrophage polarization; b
indicates M2 macrophage polarization. TME, tumor microenvironment;
MMP, matrix metalloproteinase. Created in BioRender. Zheng, B.
(2025) https://BioRender.com/dxwgq2l.
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Copy and paste a formatted citation
Spandidos Publications style
Zheng B, Han Y and Zhang H: Role of matrix metalloproteinases in the invasion of glioblastoma and drug interventions (Review). Int J Mol Med 57: 33, 2026.
APA
Zheng, B., Han, Y., & Zhang, H. (2026). Role of matrix metalloproteinases in the invasion of glioblastoma and drug interventions (Review). International Journal of Molecular Medicine, 57, 33. https://doi.org/10.3892/ijmm.2025.5704
MLA
Zheng, B., Han, Y., Zhang, H."Role of matrix metalloproteinases in the invasion of glioblastoma and drug interventions (Review)". International Journal of Molecular Medicine 57.2 (2026): 33.
Chicago
Zheng, B., Han, Y., Zhang, H."Role of matrix metalloproteinases in the invasion of glioblastoma and drug interventions (Review)". International Journal of Molecular Medicine 57, no. 2 (2026): 33. https://doi.org/10.3892/ijmm.2025.5704
Copy and paste a formatted citation
x
Spandidos Publications style
Zheng B, Han Y and Zhang H: Role of matrix metalloproteinases in the invasion of glioblastoma and drug interventions (Review). Int J Mol Med 57: 33, 2026.
APA
Zheng, B., Han, Y., & Zhang, H. (2026). Role of matrix metalloproteinases in the invasion of glioblastoma and drug interventions (Review). International Journal of Molecular Medicine, 57, 33. https://doi.org/10.3892/ijmm.2025.5704
MLA
Zheng, B., Han, Y., Zhang, H."Role of matrix metalloproteinases in the invasion of glioblastoma and drug interventions (Review)". International Journal of Molecular Medicine 57.2 (2026): 33.
Chicago
Zheng, B., Han, Y., Zhang, H."Role of matrix metalloproteinases in the invasion of glioblastoma and drug interventions (Review)". International Journal of Molecular Medicine 57, no. 2 (2026): 33. https://doi.org/10.3892/ijmm.2025.5704
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