Cellular self-organization orchestrates ferroptosis propagation.

Self-organization generates cellular patterns that guide morphogenesis, but how it regulates collective cell fate remains underexplored. We show that cellular self-organization constrains the propagation of ferroptosis, an iron-dependent form of oxidative cell death that can otherwise spread as unbounded trigger waves. The spatial patterning of cell density and alignment encodes transcriptional programs, priming cells toward ferroptosis-sensitive or -resistant fates. Low-density, misaligned regions with elevated YAP/TEAD1 activity are sensitive, whereas high-density, aligned regions with increased NRF2 expression form propagation-resistant boundaries. Cell elongation establishes a polarized distribution of oxidizable lipids, creating peroxidation hotspots at the cell poles that promote propagation along cell alignment. In silico and pharmacological perturbations reveal that pattern-dependent susceptibility and polarized lipid organization act together to constrain isotropic waves into spatially confined, anisotropic propagation. These findings identify self-organization as a systems-level mechanism governing collective homeostasis, providing a paradigm to explore how tissue-scale organization regulates cell death in development and disease.