Metabolic cell death: ferroptosis, cuproptosis, and disulfidptosis as a unified framework for targeting metabolic...

Resistance to apoptosis-targeted cancer therapies remains a major clinical hurdle. Ferroptosis, cuproptosis, and disulfidptosis represent typical forms of metabolic cell death that bypass classical apoptotic pathways, offering unprecedented opportunities to overcome such resistance. These three death modalities converge on a shared metabolic hub-the SLC7A11/cystine/GSH/NADPH axis-where disruption at different nodes steers the outcome toward ferroptosis, cuproptosis, or disulfidptosis. This interconnection is the foundation of our unified framework. While recent seminal reviews (Mao et al.) have established the conceptual framework integrating ferroptosis, cuproptosis, and disulfidptosis, the translational implementation of this framework remains fragmented. Here, we extend this established paradigm by providing a comprehensive, clinically actionable metabolic vulnerability atlas that not only systematically dissects the regulatory logic in both oncological and non-oncological settings but also, for the first time, proposes a bench-to-bedside bidirectional roadmap that prioritizes solutions for biomarker scarcity, systemic toxicity, and mechanistic heterogeneity. Crucially, we expand the framework to incorporate emerging modalities (e.g., oxeiptosis, alkalipoptosis), offering a dynamic extension to the static model. We systematically dissect their signaling networks, regulatory logic, and therapeutic strategies in both oncological and non-oncological settings. For the first time, we propose a translational research roadmap that identifies key bottlenecks across these pathways-including biomarker scarcity, systemic toxicity, and mechanistic heterogeneity-and prioritizes solutions tailored to each. Unlike existing reviews, our metabolic vulnerability atlas enables patient stratification and guides the rational design of selective modulators, supported by a bidirectional feedback loop between bench and bedside. By redefining metabolic cell death as a sabotage mechanism rather than an apoptotic process, this framework challenges the apoptosis-centric paradigm and provides a robust theoretical foundation for next-generation precision therapies that directly target the metabolic determinants of cell fate. These concepts are illustrated in an integrated schematic (Fig. 1), which sets the stage for the mechanistic and therapeutic analyses that follow.