Targeting the hepcidin-ferroportin axis in polycythemia vera: a complementary approach to clone-directed therapies.
Key claim: Hepcidin-ferroportin axis targeting (e.g., rusfertide) induces functional iron restriction that durably controls hematocrit and reduces phlebotomy need in PV as a complement to clone-directed therapy, while effects on thrombosis and disease trajectory remain unproven.
Abstract
Polycythemia vera (PV) is a clonal myeloproliferative neoplasm in which erythrocytosis, although driven by constitutive JAK2 signaling, remains dependent on iron availability. This dependency provides a rationale for therapeutic targeting of the hepcidin-ferroportin axis, whose modulation induces functional iron restriction and constrains erythropoiesis. The hepcidin mimetic rusfertide has shown durable hematocrit control and marked reduction of phlebotomy requirements across phase 2 and phase 3 studies, with predictable changes in systemic iron markers. However, current evidence is largely based on surrogate hematologic endpoints, and whether iron-directed strategies reduce thrombotic risk or modify disease trajectory remains undefined. Within this framework, iron metabolism can be viewed as a downstream, regulatable determinant of erythropoietic output, distinct from but integrated with clonal and inflammatory signaling. This review summarizes biological and clinical evidence on iron homeostasis in PV, focusing on the hepcidin-ferroportin axis and its integration with clone-directed therapies.
Why this matters
Hepcidin-ferroportin axis targeting (e.g., rusfertide) induces functional iron restriction that durably controls hematocrit and reduces phlebotomy need in PV as a complement to clone-directed therapy, while effects on thrombosis and disease trajectory remain unproven.