Copper-Iron Cell Death Axis: Mechanistic Crosstalk, Disease Implications and an Integrated Metallo-Redox-Metabolic Framework.

Cuproptosis and ferroptosis are two major forms of metal-dependent cell death, characterized by mitochondrial proteotoxicity and lipid peroxidation, respectively, and are broadly implicated in diverse disease contexts. Here, by integrating mechanistic, biological, and disease-associated evidence, we propose the metal-metabolism-redox vulnerability axis, which describes cellular states under metal stress as a continuous space defined by metal homeostasis, mitochondrial metabolism, and redox balance. Within this space, cuproptosis and ferroptosis correspond to distinct execution regions rather than independent processes. Building on this concept, we further establish a metallo-redox-metabolic framework to explain how key state variables and their coupling relationships determine execution bias and drive dynamic transitions between death modalities. This framework reframes metal-dependent cell death as a state-driven system rather than a collection of discrete pathways and provides a unified perspective for understanding its roles in complex diseases. In addition, we outline predictive and testable hypotheses and highlight the importance of multi-omics integration and artificial intelligence based modeling in capturing cellular state and enabling dynamic prediction. Collectively, this work provides a conceptual foundation for understanding metal-driven cell fate decisions and for developing state-oriented therapeutic strategies.