The Multilayered Landscape of Ferroptosis: Plasticity, Propagation, and Evolutionary Perspectives

Ferroptosis is a distinct form of regulated necrotic cell death driven by iron-dependent phospholipid peroxidation, characterized by flexible and context-dependent mechanisms rather than a single fixed linear pathway. This study elucidates the critical lipid peroxidation networks and antioxidant defense systems used in determining ferroptosis, specifically emphasizing how these mechanisms underpin the plasticity of this cell death mode and its correlation with therapeutic resistance. We examine the catastrophic propagation of ferroptosis, detailing the multi-layered amplification mechanisms-ranging from intracellular organelle crosstalk to intercellular trigger waves-that may facilitate massive tissue damage in degenerative diseases and ischemic injuries. Furthermore, the evolutionary conservation of ferroptosis-like phenomena across diverse species is summarized, underscoring its fundamental role in development and host-pathogen interactions. To conclude, we explore pivotal knowledge gaps that remain in our understanding of ferroptosis. By integrating these complex regulatory networks, this review provides a comprehensive framework for understanding ferroptosis as an adaptable, self-amplifying process, informing future efforts to modulate ferroptosis in disease contexts. Notably, this review focuses on the amplification, execution, and propagation phases of ferroptosis rather than on its initial triggering mechanisms, which remain an area of active investigation.