SMIM1 drives an alternative iron uptake pathway

SMIM1 suppresses transferrin receptor loss–induced iron deficiency by mediating clathrin-dependent endocytosis of hemoglobin, enabling an alternative iron uptake route in human cells.

• Why it matters: The canonical transferrin receptor pathway does not explain all iron homeostasis in human cells, leaving an unstudied alternative mechanism that could affect anemia and iron toxicity.
• What they did: Using a large-scale gain-of-function gene-to-trait approach, the study identified SMIM1 as a regulator of iron homeostasis and showed it binds hemoglobin via its extracellular HKCK motif for lysosomal transport and iron release.
• The result: SMIM1 expression completely suppresses iron deficiency from transferrin receptor loss, SMIM1 variants are linked to hemoglobin and erythrocyte traits in humans, and SMIM1-deficient mice show iron deficiency in early erythroid precursors under erythropoietic stress.