Social defeat stress impairs systemic iron metabolism by activating the hepcidin–ferroportin axis

Chronic psychological stress has been reported to decrease circulating iron concentrations and impair hematopoiesis. However, the underlying mechanisms remain unclear. This study aimed to investigate the effects of psychological stress on biological iron metabolism by using the social defeat stress (SDS) model, a widely used model of depression. Compared with control mice, mice subjected to SDS (SDS mice) had lower social interaction (SI) behavior. The SDS mice also showed impaired hematopoiesis, as evidenced by reduced circulating red blood cell counts, elevated reticulocyte counts, and decreased plasma iron levels. In the SDS mice, the iron contents in the bone marrow decreased, whereas those in the spleen increased, suggesting dysregulation in systemic iron metabolism. The concentrations of plasma hepcidin, an important regulator of systemic iron homeostasis, increased in the SDS mice. Meanwhile, the concentrations of ferroportin, an iron transport protein negatively regulated by hepcidin, were lower in the spleen and duodenum of the SDS mice than in those of the control mice. Treatment with dalteparin, a hepcidin inhibitor, prevented the decrease in plasma iron levels in the SDS mice. The gene expression and enzyme activity of furin, which converts the precursor hepcidin to active hepcidin, were high and positively correlated with plasma hepcidin concentration. Thus, furin activation might be responsible for the increased plasma hepcidin concentration. This study is the first to show that psychological stress disrupts systemic iron homeostasis by activating the hepcidin–ferroportin axis. Consideration of psychological stressors might be beneficial in the treatment of diseases with iron‐refractory anemia. In humans and rodents, psychological stress contributes to decreased circulating iron levels and impaired hematopoiesis, but the underlying mechanisms remain to be elucidated. Circulating iron is mainly supplied by splenic macrophages, hepatocytes, and intestinal epithelial cells as needed, all via the ferroportin, an iron transport membrane protein whose function is negatively regulated by active hepcidin (hepcidin‐ferroportin axis). Our study show that psychological stress impairs systemic iron homeostasis by increasing circulating hepcidin concentrations, probably through a furin‐dependent process.