Zinc oxide nanoparticles inhibit osteosarcoma metastasis by downregulating β-catenin via HIF-1α/BNIP3/LC3B-mediated mitophagy pathway
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Updated: Sep 22, 2025
Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
Published on: October 28, 2021
Guanping He1,2, Jing-Jun Nie3, Xiao Liu2
1Department of Orthopedics, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
Abstract:
Osteosarcoma (OS) therapy faces many challenges, especially the poor survival rate once metastasis occurs. Therefore, it is crucial to explore new OS treatment strategies that can efficiently inhibit OS metastasis. Bioactive nanoparticles such as zinc oxide nanoparticles (ZnO NPs) can efficiently inhibit OS growth, however, the effect and mechanisms of them on tumor metastasis are still not clear. In this study, we firstly prepared well-dispersed ZnO NPs and proved that ZnO NPs can inhibit OS metastasis-related malignant behaviors including migration, invasion, and epithelial-mesenchymal transition (EMT). RNA-Seqs found that differentially expressed genes (DEGs) in ZnO NP-treated OS cells were enriched in wingless/integrated (Wnt) and hypoxia-inducible factor-1 (HIF-1) signaling pathway. We further proved that Zn2+ released from ZnO NPs induced downregulation of β-catenin expression via HIF-1α/BNIP3/LC3B-mediated mitophagy pathway. ZnO NPs combined with ICG-001, a β-catenin inhibitor, showed a synergistic inhibitory effect on OS lung metastasis and a longer survival time. In addition, tissue microarray (TMA) of OS patients also detected much higher β-catenin expression which indicated the role of β-catenin in OS development. In summary, our current study not only proved that ZnO NPs can inhibit OS metastasis by degrading β-catenin in HIF-1α/BNIP3/LC3B-mediated mitophagy pathway, but also provided a far-reaching potential of ZnO NPs in clinical OS treatment with metastasis.
Insights
Zinc oxide nanoparticles (ZnO NPs) inhibit osteosarcoma (OS) metastasis by degrading β-catenin through a mitophagy pathway. This discovery offers potential for new clinical treatments for metastatic OS.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- Osteosarcoma (OS) metastasis significantly reduces patient survival rates, necessitating novel therapeutic strategies.
- While zinc oxide nanoparticles (ZnO NPs) show anti-tumor effects, their impact on OS metastasis and underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the effect of ZnO NPs on OS metastasis-related behaviors and elucidate their underlying molecular mechanisms.
- To evaluate the therapeutic potential of combining ZnO NPs with a β-catenin inhibitor for treating metastatic OS.
Main Methods:
- Preparation and characterization of well-dispersed ZnO NPs.
- Assessment of ZnO NP effects on OS cell migration, invasion, and epithelial-mesenchymal transition (EMT).
- RNA sequencing (RNA-Seq) to identify differentially expressed genes (DEGs) and enriched signaling pathways.
- Investigation of the role of β-catenin, mitophagy, and the HIF-1α/BNIP3/LC3B pathway.
- In vivo studies using a combination therapy of ZnO NPs and ICG-001 in a mouse model of OS lung metastasis.
- Tissue microarray (TMA) analysis of β-catenin expression in human OS patient samples.
Main Results:
- ZnO NPs effectively inhibited OS cell migration, invasion, and EMT.
- RNA-Seq revealed enrichment of Wnt and Hypoxia-Inducible Factor-1 (HIF-1) signaling pathways in ZnO NP-treated cells.
- Zn²⁺ released from ZnO NPs induced β-catenin downregulation via HIF-1α/BNIP3/LC3B-mediated mitophagy.
- Combined treatment with ZnO NPs and ICG-001 synergistically reduced OS lung metastasis and improved survival.
- Human OS tissues showed elevated β-catenin expression, correlating with disease progression.
Conclusions:
- ZnO NPs inhibit osteosarcoma metastasis by degrading β-catenin through the HIF-1α/BNIP3/LC3B-mediated mitophagy pathway.
- The combination of ZnO NPs and β-catenin inhibition presents a promising therapeutic strategy for metastatic osteosarcoma.
- This study highlights the significant potential of ZnO NPs in clinical applications for managing osteosarcoma metastasis.
