Erythropoiesis and iron metabolism are closely interconnected, under both physiological and pathological conditions. Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) caused by a Janus kinase-2 (JAK2) mutation, resulting in uncontrolled red blood cell production and elevated hemoglobin and hematocrit levels. In PV, iron deficiency is common and may be due to several factors, including chronic gastrointestinal bleeding, chronic inflammation, dysregulated hepcidin signaling, and therapeutic phlebotomy. Many patients exhibit low serum ferritin and low to normal hepcidin levels despite erythroid proliferation, suggesting a maladaptive iron-restricted state. This functional iron deficiency may limit erythropoiesis to some extent, but also contributes to burdensome symptoms such as fatigue, cognitive impairment, and restless leg syndrome. Novel therapeutic approaches, including hepcidin mimetics or ferroportin inhibitors, aim to restore iron homeostasis, improving quality of life and potentially reducing the need for cytoreductive therapy (drugs used to treat MPNs by reducing blood cell production) in low-risk PV patients. In secondary forms of erythrocytosis (both congenital and acquired), iron homeostasis has been less often investigated. However, exploring it may be of great interest since in these affections, iron overload could act as a hidden driver of erythrocytosis by stimulating erythroblast proliferation. Hereditary hemochromatosis (HH) is a well-known cause of iron overload. While its association with erythrocytosis has been a subject of interest, it remains incompletely understood. In this review, we will explore the complex relationship between iron (deficiency or overload, including HH) and erythrocytosis (including PV), discussing underlying mechanisms and potential therapeutic applications.
