The emerging role of ferroptosis in bone cancer eradication and tissue regeneration with tellurium-doped bioactive glass

Human osteosarcoma (OS) is a rare malignant tumor predominantly located in the long bones characterized by a poor prognosis due to limited treatment options. Currently, the first line of intervention consists of surgical resection of primary tumor combined with radiotherapy and chemotherapy, with a profound impact on patient’s life. Nonetheless, most osteosarcoma cells exhibit resistance to the latter conventional treatments, mainly stimulating apoptosis, frequently associated to the well-known epithelial-mesenchymal transition (EMT), which consists of gene expression reprogramming-associated increased invasiveness and enhanced metastatic potential. Therefore, there is an urgent need for the development of novel therapeutic strategies to completely eradicate OS cells. Recently, a new form of non-apoptotic cell death has been described, known as ferroptosis, particularly effective in cancer cells unresponsive to canonical apoptosis and characterized by a prominent mesenchymal morphology. Therefore, the induction of ferroptosis might represent a new valuable strategy to efficiently kill OS cells. In this study, we demonstrated a heterogeneous sensitivity of OS cells to ferroptosis execution, which can be attributed to the expression of ferroptosis suppressor protein 1 (FSP1), a well-known anti-ferroptotic factor. Indeed, inhibiting the activity or expression of FSP1 efficiently restores the sensitivity to ferroptosis. Additionally, our findings also suggest that other factors such as NRF2, p53, and AKRs also play a role in regulating FSP1 expression and/or influencing cancer cell resistance to ferroptosis. Therefore, the expression of FSP1 might represent a new valuable marker for predicting the sensitivity of osteosarcoma cells to ferroptosis and as a promising target for novel therapeutic interventions. Since surgical removal of primary OS frequently results in large resection of bones, the use of biomaterials to sustain the stability of remaining tissue and to stimulate bone tissue regeneration is a challenge. In this context, we explored the potential of doped-bioactive glass as novel therapeutic intervention to both eradicate malignant cells and simultaneously promote bone tissue regeneration. Bioactive glass (BAG) has been extensively studied and employed in the field of regenerative medicine, due to its osseointegration properties and ability to improve bone tissue regeneration. Of note, we found that the incorporation of tellurium (Te) in BAG resulted in selective OS cells killing through ferroptosis while preserving the viability of human mesenchymal stem cells (hBMSCs), and stimulating their osteodifferentiation. Although the molecular basis of Te toxicity has not yet been fully elucidated, our results suggest that Te-BAG-induces lipid peroxidation, does not require iron overload, and potentially directly affects the functionality of FSP1.