Iron deficiency induces maturation-dependent loss of pancreatic β-cells
Summary
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. © 2026. The Author(s).
| Authors | Van Mulders A, Willems L, Coenen S, Bourgeois S, Yi X, Tong Y, Leuckx G, Heremans Y, Pierreux J, Degroote L, Sawatani T, Vinci C, Ates G, Massie A, Carlotti F, de Koning E, Mandrup-Poulsen T, Zelinsky C, Goderis S, Ghesquière B, Scharfmann R, Cnop M, De Leu N, Staels W |
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| Journal | Nature communications |
| Publication Date | 2026 Feb 16;17(1) |
| PubMed | 41698932 |
| PubMed Central | PMC13022395 |
| DOI | 10.1038/s41467-026-69574-y |