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. 2026 Jan 13;16:1726210. doi: 10.3389/fimmu.2025.1726210

Figure 1.

Diagram illustrating the iron metabolism process in a drug-resistant cancer cell. It shows transferrin binding to TfR1, initiating endocytosis. Inside, Fe3+ converts to Fe2+ in an acidic environment, then released by DMT1. Iron regulatory signals involve IRP1 and IRP2. Ferritin stores Fe3+, and autophagosomes assist in degradation. This process relates to ferroptosis, lipid peroxidation, and the labile iron pool, leading to cancer cell death through membrane damage and lipid peroxide accumulation.

Schematic illustration of iron metabolism dysregulation in drug-resistant cancer cells leading to ferroptosis. Transferrin-bound Fe³+ binds to transferrin receptor 1 (TfR1) on the cell membrane; iron regulatory proteins (IRP1/IRP2) upregulate TfR1 transcription/translation, promoting endocytosis of the transferrin-iron complex. In the acidic endosomal environment (pH 5.5–6.0), Fe³+ dissociates, is reduced to Fe²+ by STEAP3, and is exported to the cytosol via DMT1. Meanwhile, nuclear receptor coactivator 4 (NCOA4) recognizes ferritin heavy chain 1 (FTH1) of the ferritin complex (FTH1-FTL, storing ~4,500 Fe³+ ions), mediating ferritin sequestration into autophagosomes. Autophagosome-lysosome fusion triggers ferritin degradation by cathepsin B, releasing additional Fe³+ (subsequently reduced to Fe²+). The accumulated Fe²+ expands the labile iron pool (LIP), mediating the Fenton reaction to generate hydroxyl radicals (•OH). These radicals induce lipid peroxidation, leading to phospholipid hydroperoxide (PLOOH) accumulation, membrane damage, and ultimately ferroptosis in drug-resistant cancer cells.