Ferroptosis, cuproptosis, and metal ion-modulated cytotoxicity in osteosarcoma: regulatory mechanisms and emerging therapeutic strategies.

Osteosarcoma is characterized by early metastatic potential, frequent postoperative recurrence, and resistance to conventional chemotherapy, and therapeutic progress remains limited. Osteosarcoma may have exploitable vulnerabilities due to metal homeostasis and redox control dysregulation. However, metal-associated cytotoxic processes do not constitute a single class of regulated cell death. This review examines ferroptosis and cuproptosis as mechanistically defined metal-dependent regulated cell-death modalities and distinguishes them from broader metal ion-modulated cytotoxic processes. Ferroptosis is due to iron-dependent phospholipid peroxidation and the collapse of antioxidant defenses, while cuproptosis is induced by the interaction of copper with lipoylated mitochondrial proteins, which induces protein aggregation, loss of iron-sulfur cluster proteins, and proteotoxic stress. In addition, perturbations in metal homeostasis are likely to affect chemosensitivity, immune responses and the osteolytic microenvironment; these effects may be either beneficial or adverse depending on the cellular compartment. Preclinical agents, including small molecules, nanomedicine-based delivery systems, metal-active scaffolds and immunotherapy combinations, have demonstrated remarkable potential but varying degrees of mechanistic validation and translational maturity. Osteosarcoma-specific mechanistic evidence is currently strongest for ferroptosis, whereas evidence for canonical cuproptosis remains limited and is concentrated mainly in material-based experimental systems with incomplete mechanistic validation. Studies in the future should combine molecular subtype with intraosseous microenvironmental context, cell-type-specific toxicity and therapeutic response to classify osteosarcoma subgroups for prospective evaluation of metal-targeted treatments.