<p>Despite advances in treatment modalities, current bone tumor therapies still face significant challenges, including severe side effects of conventional approaches, poor survival rates and high rates of tumor recurrence. We previously identified a strong cytotoxic effect of 45S5-bioactive glass (BG) particles on bone tumor cells, indicating possible therapeutic properties of these materials. In order to identify the mechanisms that trigger tumor cell death, we investigated the impact of 45S5-BG on bone tumor cells compared to non-neoplastic cells. Regardless of cell type, BG treatment induced oxidative stress and increased ROS production. Fluorescently labeled SiO₂ particles were rapidly internalized by both cell types. Tumor cell-specific responses included elevation of calcium levels, activation of MAP- and AKT-kinase as well as the release of LDH and ATP from the cells. Apoptosis, pyroptosis and necroptosis could be excluded as possible cell death mechanisms due to the lack of caspase activation and a RIPK3 deficiency of the tumor cells. Rather, we identified an important role of lysosomes and the requirement of intact V-ATPase activity. Together with a strong increase in intracellular Fe²⁺ and MDA levels triggered by BG-treatment, these data strongly suggest that ferroptosis is the main cause of tumor cell-specific death. In combination with the known beneficial effects of BGs on bone regeneration, our data point to a potential therapeutic strategy for promoting bone repair while simultaneously reducing tumor recurrence. Furthermore, understanding the underlying mechanisms and the option to modify the glass composition could help to develop even more potent BG variants.</p>