Intercellular propagation of ferroptosis

• Ferroptosis propagates between cells through multiple mechanisms including ROS trigger waves, membrane contact-dependent transmission, paracrine signaling (PAF-PAFAH2, galectin-13), and extracellular vesicles. • The ability of ferroptosis to propagate is inducer-specific, with erastin but not RSL3 triggering intercellular spread, reflecting fundamental differences in upstream metabolic stress requirements. • Ferroptosis propagation exhibits context-dependent dual roles in disease: promoting cluster-killing effects in cancer therapy while exacerbating tissue damage in ischemia-reperfusion injury and neurodegeneration. • Senescent cells create tissue microenvironments primed for ferroptosis propagation through iron accumulation, impaired antioxidant defenses, and pro-ferroptotic SASP factors. • Understanding propagation mechanisms enables therapeutic strategies to either enhance ferroptosis spread for cancer treatment or block it to protect healthy tissues in acute injuries and age-related diseases. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, was initially characterized as a cell-autonomous process. However, emerging evidence demonstrates that ferroptotic signals can propagate between cells, triggering synchronized death events with significant pathophysiological implications. This review examines the molecular mechanisms underlying intercellular ferroptosis propagation, including ROS-mediated trigger waves, contact-dependent lipid peroxidation transmission, paracrine signaling, and extracellular vesicle-mediated communication. We analyze the dual roles of ferroptosis propagation in the tumor microenvironment and its contribution to tissue damage in ischemia-reperfusion injury and neurodegeneration. Understanding these propagation mechanisms offers novel therapeutic opportunities for precisely modulating cellular death responses across diverse disease contexts.