Nuclear Receptor Nur77 Orchestrates Hematopoietic Lineage Commitment to Avert Anemia in Diabetes

Anemia is a prevalent but poorly understood complication of diabetes mellitus. Here, we identify orphan nuclear receptor Nur77 as a critical suppressor of diabetic anemia. Nur77 expression was downregulated in hematopoietic stem and progenitor cells (HSPCs) from diabetic patients with anemia. In multiple diabetic mouse models, knockout of Nur77 induced anemia, a phenotype recapitulated by bone marrow transplantation. Mechanistically, Nur77 functioned as a transcriptional repressor in HSPCs, whose deficiency, together with diabetes-associated epigenetic modifications, enhanced chromatin accessibility and expression of genes involved in myeloid leukocyte differentiation. Consequently, this led to myeloid leukocyte-biased differentiation of HSPCs at the expense of erythroid lineage. Pharmacological upregulation of Nur77 with its agonist cytosporone B (Csn-B) effectively prevented anemia in diabetic mice. Clinically, Nur77 levels in HSPCs of diabetic patient negatively correlated with anemia occurrence. Collectively, our findings reveal a novel Nur77-mediated pathway in diabetic anemia pathogenesis and propose Nur77 as a new therapeutic target.