Iron deficiency induces maturation-dependent loss of pancreatic ß-cells.

Pancreatic ß-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 ß-cell development remains unclear. Here, we identify a maturation-dependent requirement for iron in mouse and human ß-cells. Using chemical chelation and genetic disruption of transferrin receptor (TFRC)-mediated uptake, we show that immature ß-cells depend on iron during metabolic transition to functional maturity. Iron restriction at this stage impairs oxidative metabolism and compromises survival. In contrast, mature ß-cells remain resilient to iron depletion, revealing a developmental switch in iron dependency. These findings establish iron as a key metabolic cue in ß-cell development and suggest strategies to generate fully functional stem cell-derived ß-cells for diabetes modeling and cell replacement therapy. Overall design: We performed bulk-RNA sequencing on magnetic-activated cell sorting (MACS)-purified iPSC-derived stage 7 ß-like cells exposed to DFO (100 µM, Vehicle H2O) with a composition of 75% INS single positive cells quantified by immunocytochemistry staining, n=4 independent differentiations.