Protein iron transporters as potential therapeutic targets in cancer: A review

Iron is an essential trace element crucial for DNA synthesis, oxygen transport, and redox processes. In mammals, its homeostasis is strictly regulated by protein transporters like transferrin, solute carriers, and ATP-binding cassette proteins. They are specialized transmembrane proteins that facilitate iron uptake, export and intracellular trafficking. Dysregulation of these transporters can increase intracellular iron, boosting reactive oxygen species production and genetic instability, thereby promoting cancer hallmark processes such as sustained proliferation, apoptosis evasion, metastasis, and resistance to therapy. Transporters such as SLC11A2, SLC39A14, and ABCB7 notably modulate oncogenic pathways including JAK/STAT, TGF-β, Wnt, and HIF signaling. Such dysfunction reprograms cellular metabolism and signaling, contributing to cancer progression and therapeutic failure. Epigenetic modifications and polymorphisms in these transporters further enhance tumor aggressiveness and chemoresistance. Recent studies highlight the role of iron transporters in ferroptosis, an iron-dependent form of cell death, offering new therapeutic avenues. Targeting these transporters with small molecule inhibitors, microRNA therapies, and natural products has shown promise in preclinical models. This review explores the diverse roles of protein iron transporters in oncogenesis, emphasizing their potential as prognostic biomarkers and therapeutic targets.