Journal Article

Iron deficiency induces maturation-dependent loss of pancreatic β-cells

Ghesquière, Bart, Mandrup-Poulsen, Thomas, Tong, Yue, Degroote, Laure, Heremans, Yves, Scharfmann, Raphael, Yi, Xiaoyan, Coenen, Sophie, Ates, Gamze, Goderis, Steven, Staels, Willem, De Leu, Nico, Willems, Lien, Leuckx, Gunter, de Koning, Eelco, Bourgeois, Stephanie, Van Mulders, Annelore, Carlotti, Françoise, Cnop, Miriam, Sawatani, Toshiaki, Vinci, Chiara, Zelinsky, Clara, Massie, Ann, Pierreux, Julie

2026

Overview

Pancreatic β-cells maintain glucose homeostasis by secreting insulin in response to rising blood glucose, a process fueled by mitochondrial ATP production. Iron, a core cofactor in the electron transport chain, is essential for this metabolic coupling. While the cytotoxic effects of iron overload are well known, the role of iron sufficiency during β-cell development remains unclear. Here, we identify a maturation-dependent requirement for iron in mouse and human β-cells. Using chemical chelation and genetic disruption of transferrin receptor (TFRC)-mediated uptake, we show that immature β-cells depend on iron during metabolic transition to functional maturity. Iron restriction at this stage impairs oxidative metabolism and compromises survival. In contrast, mature β-cells remain resilient to iron depletion, revealing a developmental switch in iron dependency. These findings establish iron as a key metabolic cue in β-cell development and suggest strategies to generate fully functional stem cell-derived β-cells for diabetes modeling and cell replacement therapy. This study reports a maturation-dependent requirement for transferrin receptor -mediated iron uptake in pancreatic β-cells, whereby iron deficiency disrupts metabolic integrity and survival in developing cells but not in mature β-cells. The results show iron is a cue for β-cell maturation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/1 / 14/19 / 14/28 / 14/34 / 14/63 / 38/77 / 38/88 / 38/90 / 38/91 / 42/100 / 45/29 / 49 / 49/31 / 49/88 / 59 / 631/80/304 / 64 / 64/60 / 692/163/2743/137 / 82/51 / 82/80 / 96/2 / Age / Animals / Beta cells / Cell Differentiation / Cell survival / Cells / Chelation / Cytotoxicity / Diabetes / Diabetes mellitus / Electron transport / Electron transport chain / Gene expression / Glucose / Glucose - metabolism / Homeostasis / Humanities and Social Sciences / Humans / Insulin / Insulin - metabolism / Insulin-Secreting Cells - cytology / Insulin-Secreting Cells - drug effects / Insulin-Secreting Cells - metabolism / Iron / Iron - metabolism / Iron Deficiencies / Iron deficiency / Maturation / Metabolism / Mice / multidisciplinary / Nutrient deficiency / Oxidative metabolism / Pancreas / Proteins / Receptors / Receptors, Transferrin - genetics / Receptors, Transferrin - metabolism / Science / Science (multidisciplinary) / Stem cells / Survival / Transferrin / Transferrins