Zinc oxide nanoparticles inhibit osteosarcoma metastasis by downregulating β-catenin via HIF-1α/BNIP3/LC3B-mediated mitophagy pathway.

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 Zn 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.