Dynamic protein trafficking shapes ferroptosis sensitivity and immunogenicity.

Ferroptosis is generally described as a regulated form of cell death associated with metabolic dysregulation and iron-dependent lipid peroxidation. Beyond gene expression and enzymatic activity, accumulating evidence indicates that ferroptosis sensitivity is governed by dynamic protein trafficking between subcellular compartments. Under ferroptotic stress, proteins redistribute among organelles, enabling context-dependent functions that either amplify lipid peroxidation and iron toxicity or reinforce antioxidant defense. Crucially, this spatial reorganization not only dictates the execution of ferroptosis but also determines its immunogenicity by controlling the intracellular sequestration, membrane targeting, and extracellular release of immunomodulatory factors. This review synthesizes recent advances showing how protein trafficking integrates lipid metabolism, iron handling, mitochondrial function, redox control, and immune signaling, and proposes protein translocation as a unifying spatial principle that shapes ferroptosis sensitivity and immunogenic outcomes.