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

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.