Navigating Transition Metal‐Dependent Cell Death: Mechanisms, Crosstalk, and Future Directions

Regulated cell death is fundamental to cellular homeostasis, with metal-dependent pathways emerging as critical mechanisms influencing cell fate decisions. This comprehensive review examines the emerging landscape of metal-dependent regulated cell death pathways, focusing on ferroptosis, cuproptosis, and the hypothetical concept of "cobaltosis." Ferroptosis, characterized by iron-catalyzed lipid peroxidation and glutathione depletion, has emerged as a critical pathway in cancer, neurodegeneration, and ischemia-reperfusion injury. Cuproptosis, a recently defined copper-induced death mechanism, operates through direct binding of copper to lipoylated mitochondrial proteins, causing proteotoxic stress and metabolic collapse. Evidence for cobaltosis is critically evaluated as a potential distinct regulated cell death pathway, cobalt's known cellular impacts are examined, and a rigorous experimental framework is proposed for its investigation and validation as a distinct entity. This review comparatively analyzes the core mechanisms, highlighting the distinct roles of reactive oxygen species and mitochondria in each pathway. The intricate crosstalk and divergence among these death modalities are explored, introducing the concept of a "metal death code" that dictates the cellular fate in response to specific metal stresses. Furthermore, advanced technologies for detecting and dissecting these pathways are discussed, and their significant translational potential for treating diseases characterized by metal dyshomeostasis is considered, such as cancer and neurodegeneration.