Transferrin receptor 1 shedding by the pro-inflammatory iRhom-ADAM17 complex and ADAM10 regulates cellular iron uptake and ferroptosis

  • Exp Mol Med. 2026 Jun;58(6):1824-1837. doi: 10.1038/s12276-026-01731-1.
Katharina Schun  1 ,  Cindy Rinkens  1 ,  Daniel Mehling  1  2 ,  Yan Yu  1 ,  Sarah Knapp  1 ,  Carolin Peschke  1 ,  Friederike Sonnabend  1 ,  Christine Lux  1 ,  Alessa Pabst  1 ,  Laura Charlier  1 ,  Neele Schumacher  3 ,  Aaron Babendreyer  1 ,  Andreas Ludwig  1 ,  Stefan Düsterhöft  4  5
Affiliations
  • 1. Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
  • 2. GENEART AG/Thermo Fisher Scientific, Regensburg, Germany.
  • 3. Institute of Biochemistry, Medical Faculty, Kiel University, Kiel, Germany.
  • 4. Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany. [email protected].
  • 5. Medical Faculty, Campus Düsseldorf/Krefeld, HMU Health and Medical University, Düsseldorf, Deutschland. [email protected].
PMID: 42243530 DOI: 10.1038/s12276-026-01731-1
Abstract

Iron homeostasis is a tightly regulated mechanism, wherein the uptake, transport, storage and export of iron are stringently controlled. Dysregulation and excessive iron uptake lead to iron-dependent programmed cell death called Ferroptosis, a promising future Cancer therapy target. Cellular iron uptake is limited by the surface presence of membrane-bound Transferrin Receptor 1 (TfR1). Soluble TfR1 is used as a major clinical marker to differentiate anemia types. Here we identify iRhoms, the regulatory interactors of the surface protease ADAM17, as substrate platforms. They bind TfR1 and facilitate ADAM17-mediated proteolytic TfR1 release (TfR1 shedding). Thereby, the iRhom-ADAM17 complex regulates TfR1 surface levels. Notably, TfR1 preferentially binds to pro-inflammatory iRhom2 over iRhom1, with the cytosolic N terminus of iRhom serving as a critical binding determinant. By CRISPR-Cas9-based knockout and pharmacological inhibition in vitro, in human primary endothelial cells as well as in ex vivo human lung slices, we also demonstrate that TfR1 is a shared substrate of ADAM10 and ADAM17. Functionally, we found that ADAM17-dependent TfR1 shedding reduces excessive iron uptake. By live cell imaging, we identified TfR1 shedding as a protective mechanism against Ferroptosis. Moreover, reduced TfR1 shedding correlaśtes with elevated serum iron levels in ADAM17-hypomorphic mice, highlighting its systemic relevance for patho(physiological) iron homeostasis. iRhom-ADAM17 complex and ADAM10-shed TfR1. Cellular iron uptake is facilitated by TfR1. TfR1 interacts with the substrate platform iRhom, which is a regulator of the protease ADAM17. The iRhom-ADAM17 complex and ADAM10 cleave TfR1, thereby releasing soluble TfR1. By this, iron overloaded is prevented. Therefore, ectodomain shedding of TfR1 is a protective mechanism to hinder Ferroptosis.

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