The study explores the mechanism of large-scale cell death, specifically ferroptosis, which is an iron- and lipid-peroxidation-dependent form of cell death. Ferroptosis can propagate across human cells over long distances (≥5 mm) at a constant speed (around 5.5 μm min−1) through trigger waves of reactive oxygen species (ROS). The research identifies ROS feedback loops (Fenton reaction, NADPH oxidase signaling, and glutathione synthesis) as key regulators of ferroptotic wave propagation. By suppressing cystine uptake, which activates these ROS feedback loops, cells become bistable, allowing ferroptosis to spread as trigger waves. This mechanism overcomes the spatial limitations of simple diffusion, enabling large-scale cell death events. The findings are supported by experiments in avian limb development, where ferroptosis is involved in muscle remodeling, demonstrating its role in tissue sculpting during embryogenesis. The study highlights the importance of ferroptosis in coordinating global cell death events and provides insights into its potential involvement in both developmental processes and pathological conditions.The study explores the mechanism of large-scale cell death, specifically ferroptosis, which is an iron- and lipid-peroxidation-dependent form of cell death. Ferroptosis can propagate across human cells over long distances (≥5 mm) at a constant speed (around 5.5 μm min−1) through trigger waves of reactive oxygen species (ROS). The research identifies ROS feedback loops (Fenton reaction, NADPH oxidase signaling, and glutathione synthesis) as key regulators of ferroptotic wave propagation. By suppressing cystine uptake, which activates these ROS feedback loops, cells become bistable, allowing ferroptosis to spread as trigger waves. This mechanism overcomes the spatial limitations of simple diffusion, enabling large-scale cell death events. The findings are supported by experiments in avian limb development, where ferroptosis is involved in muscle remodeling, demonstrating its role in tissue sculpting during embryogenesis. The study highlights the importance of ferroptosis in coordinating global cell death events and provides insights into its potential involvement in both developmental processes and pathological conditions.