Membrane instability as a propagation-repair imbalance in ferroptosis

Ferroptosis is commonly described as an iron-dependent form of cell death driven by lipid peroxidation. However, lipid peroxidation is pervasive across aerobic systems, whereas catastrophic membrane rupture is selective. Membrane fate cannot be inferred from oxidative burden alone. Instead, failure reflects a dynamical transition that occurs when radical propagation outpaces membrane repair within a metabolically sustained, nonequilibrium system. We propose a propagation-repair framework organized around a conceptual propagation-repair state (Φ), in which propagation capacity captures lipid radical amplification and spatial spread, and repair capacity integrates hydroperoxide detoxification, radical termination, lipid remodeling, and membrane resealing. In biochemical terms, Φ approximates the ratio between lipid peroxidation flux and NAD(P)H-dependent detoxification capacity, linking membrane stability to redox-constrained metabolic throughput. This framework suggests that ferroptotic commitment may arise from cofactor-limited detoxification rather than discrete molecular triggers and can be uncoupled from bulk ROS levels. Ferroptosis thus represents a regime of membrane failure defined by flux imbalance under constrained redox buffering.