Transferrin receptor 1: an emerging therapeutic target in cancer beyond iron metabolism

Iron is an indispensable trace element for maintaining normal physiological functions in the body, participating in key biological processes such as energy metabolism, DNA synthesis, and damage repair. Under normal physiological conditions, cells tightly regulate iron homeostasis to prevent iron overload-induced oxidative stress and DNA damage. In contrast, tumor cells undergo iron metabolic reprogramming to adapt to their aberrant proliferation and elevated metabolic levels. By upregulating iron uptake and storage pathways, they elevate intracellular iron levels, providing essential cofactors for accelerated DNA synthesis and mitochondrial energy production, thereby meeting the material and energy demands of malignant growth. As an essential regulator of iron acquisition, transferrin receptor 1 (TFR1) binds transferrin (TF) and enters the cell through clathrin-mediated endocytosis to deliver ferric iron (Fe³⁺). Internalized TFR1 returns to the cytoplasmic membrane via the recycling pathway, sustaining surface receptor levels and enabling continued iron uptake. Owing to this mechanism, TFR1 has emerged as a prominent target for anticancer drug development. This review focuses on the molecular mechanisms regulating TFR1, from transcriptional regulation to translational expression, with a focus on its biological roles in iron metabolism and malignant progression. Furthermore, we summarize various TFR1-targeted antitumor strategies based on current research, providing a theoretical foundation for the development of novel anticancer therapeutics.