Redundant or resilient? A systems view of ferroptosis surveillance mechanisms.

Ferroptosis is an iron-dependent form of regulated necrosis driven by phospholipid peroxidation. Its suppression relies on a multilayered surveillance system-including neutralizing phospholipid peroxides, terminating the propagation of lipid peroxidation, and limiting the substrates for phospholipid peroxidation-that operates across subcellular compartments and adapts to tissue-specific demands. Rather than functioning redundantly, these defense mechanisms are deployed in a resilient, context-specific manner, shaped by the metabolic profiles, redox states, and regenerative capacities of distinct cell types. Intact ferroptosis surveillance may be especially crucial for post-mitotic cells such as neurons, as its failure can lead to oxidative damage and irreversible degeneration. In contrast, cancer cells actively acquire ferroptosis resistance by upregulating antioxidant networks and reprogramming lipid metabolism, thereby creating a therapeutic vulnerability. Understanding how ferroptosis surveillance is spatially organized and dynamically regulated provides a framework for precision interventions-restoring redox resilience in degenerative disease or selectively inducing ferroptosis in tumors.