REVIEW article
Front. Med.
Sec. Hematology
Therapeutic Targeting of the Hepcidin-Ferroportin Axis and Erythropoietic Modulators: A narrative review
Provisionally accepted
- 1College of Pharmacy, Alfaisal University, Riyadh, Saudi Arabia
- 2College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Iron homeostasis represents a critical regulatory network in hematologic diseases, with dysregulation contributing to diverse pathological conditions ranging from iron-loading anemias to hematologic malignancies. The hepcidin molecule acts as a master regulator and works in conjunction with its sole iron exporter, the ferroportin channel, orchestrating systemic iron balance through intricate molecular mechanisms involving bone morphogenetic protein (BMP) signaling, erythroferrone, and transmembrane serine protease 6 (TMPRSS6). Recent advances have identified ferroptosis, an iron-dependent cell death pathway, as both a pathogenic mechanism and therapeutic target in hematologic disorders. This narrative review synthesizes current understanding of iron regulatory pathways and examines emerging therapeutic approaches targeting hepcidin-ferroportin dysfunction, erythroferrone modulation, and ferroptosis induction. Novel agents, including luspatercept, matriptase-2 inhibitors, and anti-hemojuvelin antibodies, represent promising interventions for conditions characterized by ineffective erythropoiesis and iron maldistribution. The integration of pharmacogenomic approaches and precision medicine strategies offers potential for optimized therapeutic outcomes in iron-related hematologic diseases. Critical evaluation of clinical trial evidence reveals both therapeutic promise and implementation challenges, highlighting the need for continued mechanistic research and translational development. Future directions emphasize combination therapeutic strategies, biomarker-driven patient stratification, and the development of targeted interventions addressing the complex interplay between iron metabolism, inflammation, and hematopoietic function.
Keywords: hepcidin, Ferroportin, iron metabolism, Erythroferrone, ferroptosis, Luspatercept, TMPRSS6, hematologic disorders
Received: 16 Oct 2025; Accepted: 25 Nov 2025.
Copyright: © 2025 Mansour, Hajjar and Sajid. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Muhammad Raihan Sajid
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