Enhanced stem cell-derived pancreatic β cell production through mitochondrial metabolic reprogramming improves islet cell therapy for diabetes

The scarcity of functional transplantable pancreatic islets remains a central limitation for curative cell replacement therapies for diabetes. Although human pluripotent stem cells provide a theoretically unlimited source of β cells, intrinsic metabolic constraints that restrict efficient endocrine lineage commitment and functional maturation are poorly defined. We combined metabolic pathway interrogation with functional and in vivo analyses to examine how mitochondrial redox signaling influences endocrine specification during human pluripotent stem cell differentiation. Targeted modulation of mitochondrial reactive oxygen species–linked arachidonic acid and eicosanoid metabolism was used to assess its impact on β-cell differentiation, maturation, and therapeutic performance following transplantation. We identify a previously unrecognized mitochondrial reactive oxygen species–driven arachidonic acid/12-hydroxyeicosatetraenoic acid metabolic axis that functions as a metabolic checkpoint limiting endocrine lineage commitment. Disruption of this pathway markedly enhances the generation of stem cell–derived β cells and accelerates their functional maturation, resulting in improved glucose-responsive insulin secretion in vitro. Notably, β cells produced through this metabolic reprogramming strategy restore normoglycaemia more rapidly and robustly after transplantation into diabetic mice than cells generated using conventional differentiation protocols. These findings define a mechanistic link between mitochondrial redox signaling and eicosanoid metabolism in β-cell fate control and establish metabolic pathway engineering as a powerful strategy to improve the efficacy of stem cell–based islet replacement therapies for diabetes.