Mitophagy at the intersection of ferroptosis and cuproptosis in osteosarcoma: Molecular interactions and therapeutic...

Osteosarcoma is the most common primary malignant bone tumor in adolescents and young adults. Its pronounced aggressiveness, metabolic reprogramming features, and the development of acquired resistance to chemotherapy severely limit the long-term efficacy of current therapeutic strategies. In recent years, the concept of metal ion-dependent regulated cell death has provided a novel theoretical framework for understanding cell fate regulation in osteosarcoma. Among these mechanisms, ferroptosis and cuproptosis are characterized by iron homeostasis-driven uncontrolled lipid peroxidation and copper-dependent mitochondrial proteotoxic stress, respectively. Both processes are closely associated with the metabolic phenotype, invasive behavior, and therapeutic responsiveness of osteosarcoma. However, the potential synergistic or antagonistic interactions between ferroptosis and cuproptosis, as well as their upstream regulatory networks in osteosarcoma, remain insufficiently integrated and systematically elucidated. Mitophagy, a critical process for maintaining mitochondrial quality control and metabolic homeostasis, is increasingly recognized as a central hub linking multiple forms of metal-dependent cell death. On the one hand, mitophagy dynamically modulates the threshold of ferroptosis by regulating mitochondrial ROS production, intracellular iron pool distribution, and lipid metabolic pathways. On the other hand, through its regulation of tricarboxylic acid cycle activity, lipoylated protein homeostasis, and mitochondrial metal-buffering capacity, mitophagy may exert bidirectional regulatory effects on cuproptosis as well. Under specific metabolic contexts, dysregulated mitophagy may serve as a critical prerequisite for amplifying the crosstalk between ferroptosis and cuproptosis. This review systematically summarizes recent advances in the study of mitophagy, ferroptosis, and cuproptosis in osteosarcoma. By focusing on mitochondrial metabolic reprogramming, metal homeostasis regulation, and programmed cell death networks, we comprehensively dissect the molecular mechanisms underlying the interplay among these processes. Furthermore, we discuss the potential therapeutic value of targeting the mitophagy-ferroptosis-cuproptosis axis to overcome osteosarcoma aggressiveness and chemoresistance, thereby providing a theoretical basis and conceptual framework for precision therapeutic strategies centered on mitochondrial and metal metabolism reprogramming.