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

www.nature.com/emm ARTICLE OPEN Transferrin receptor 1 shedding by the pro-inflammatory iRhom–ADAM17 complex and ADAM10 regulates cellular iron uptake and ferroptosis Katharina Schun 1, Cindy Rinkens1, Daniel Mehling1,2, Yan Yu1, Sarah Knapp 1, Carolin Peschke1, Friederike Sonnabend1, Christine Lux1, Alessa Pabst1, Laura Charlier1, Neele Schumacher3, Aaron Babendreyer1, Andreas Ludwig1 and Stefan Düsterhöft 1,4 ✉ 1234567890();,: © The Author(s) 2026 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 ADAM17hypomorphic mice, highlighting its systemic relevance for patho(physiological) iron homeostasis. Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-026-01731-1 Graphical Abstract 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. 1 Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany. 2GENEART AG/Thermo Fisher Scientific, Regensburg, Germany. 3Institute of Biochemistry, Medical Faculty, Kiel University, Kiel, Germany. 4Medical Faculty, Campus Düsseldorf/Krefeld, HMU Health and Medical University, Düsseldorf, Deutschland. ✉email: Received: 14 October 2025 Revised: 3 February 2026 Accepted: 8 March 2026 K. Schun et al. 2 INTRODUCTION Iron (Fe) is an essential nutrient required by all living organisms, playing a critical role in various biological processes throughout evolution. It is a key component of hemoglobin, and beyond its involvement in oxygen transport, iron also contributes to diverse metabolic processes and cellular functions such as mitochondrial respiration, immune function and DNA synthesis1. While iron is essential for various biological processes, excessive iron accumulation can result in the generation of reactive oxygen species, thereby inducing oxidative stress. Such oxidative stress is harmful for the cell and can induce ferroptosis, a recently discovered form of iron-dependent programmed cell death2. Iron homeostasis and ferroptosis are critically linked to a variety of (patho)physiological processes such as infection control, autoimmunity, inflammation, aging, neurodegeneration and tumor suppression. Strikingly, ferroptosis-inducing drugs are already used in clinical trials for antitumor treatment3. Although ferroptosis is a key cellular process with crucial systemic relevance, the underlying regulatory mechanisms are still not completely understood. Given that both iron overload and iron deficiency pose substantial health risks, iron homeostasis is tightly regulated to control its uptake, transport, storage and export1,4. The cellular iron uptake is largely mediated by transferrin (Tf) receptor 1 (TfR1)5,6. TfR1-dependent iron uptake is directly related to the surface expression of TfR1, which can be controlled in the long term by gene expression4. Rapid reduction of surface TfR1 can be achieved by cleavage of its ectodomain and subsequent release of soluble TfR17, a general process that occurs with many surface proteins and is known as ectodomain shedding8. Importantly, circulating, solubilized TfR1, present in the bloodstream, serves as a critical marker for diagnosing iron deficiency. It is the main diagnostic marker to reliably differentiate between iron deficiency anemia and anemia of chronic disorders or anemia of chronic renal failure9. Moreover, it is a well-established diagnostic marker for erythropoietic activity10. Yet, the underlying molecular mechanisms of TfR1 shedding are poorly understood (Fig. 1a). Pharmacological data suggest that members of the metalloproteinase family can be implicated in TfR1 shedding11. However, the identity of the responsible sheddases is still lacking. A disintegrin and metalloproteinase (ADAM)10 and ADAM17 are key shedding enzymes involved in many fundamental (patho) physiological processes, including development, differentiation, regeneration and inflammatory response12–15. This is due to their broad, in some cases overlapping, substrate spectrum, which includes membrane-bound forms of various cytokines (for example, tumor necrosis factor (TNF)), adhesion molecules (for example, L-selectin), growth factors (for example, epidermal growth factor (EGF) and transforming growth factor alpha (TGFα)) and receptors (for example, interleukin 6 receptor (IL6R))16. Hence, these ADAMs have to be tightly regulated. For ADAM17, the pseudoproteases iRhom1 and iRhom2 play a crucial role in its maturation and regulation17–19. Both iRhom1 and iRhom2 are catalytically inactive proteins belonging to the rhomboid superfamily of intramembrane proteases20. They form a complex with ADAM17 and promote its trafficking to the cell surface21. Recently, it has also been suggested that iRhoms serve not only as a transport and regulatory hub for ADAM17 but are also involved in ADAM17 substrate specificity, in addition to ADAM17’s direct substrate recognition functions22,23. However, a detailed understanding of the substrate recognition and specificity by the ADAM17-iRhom complex is still missing. Here, we identify iRhoms as substrate platforms, which bind TfR1, leading to ADAM17-mediated shedding. We also define the cytosolic N-terminal region of iRhoms as a necessary TfR1 binding determinant. Furthermore, we identify TfR1 as a shared substrate of ADAM17 and ADAM10 through pharmacological inhibition in model cell lines, primary endothelial cells and h (...truncated)