The rise of reducing reagent-resistant TfR1 dimer marks ferroptosis

Ferroptosis is an iron-dependent type of cell death caused by excessive membrane lipid peroxidation. It remains a challenge to detect ferroptotic cells, especially in in vivo settings, hindering translational studies. Here we discover that a reducing reagent-resistant (3R) dimer of the transferrin receptor 1 (TfR1) is a highly specific indicator for lipid peroxidation. The 3R dimer is elevated in cells when ferroptosis is induced, either by pharmacological agents or by genetic perturbations. Furthermore, the 3R dimer can be used to detect disease-associated ferroptosis in tissue and in extracellular vesicles isolated from mouse or patient plasma. Given the near-ubiquitous expression of TfR1, we posit that the 3R dimer may function as a ferroptosis marker with widespread potential utility for basic and translational studies. He et al. report the upregulation of a reducing reagent-resistant form of the transferrin receptor 1 dimer during lipid peroxidation and demonstrate its utility in detecting ferroptosis in tissue lysates and extracellular vesicles from mice and humans.