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Microorganisms
Volume 13
Issue 8
10.3390/microorganisms13081859
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Pharmacologic Inhibition of Erythrocyte Ferroportin Expression Exacerbates Plasmodium Infection

by
Sareh Zeydabadinejad
1,
Benjamin Frederick Theis
1,
Jun Sung Park
1,
Amira F. Gohara
2,
Matam Vijay-Kumar
1,
Beng San Yeoh
1 and
Piu Saha
1,*
1
Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
2
Department of Pathology, University of Toledo Medical Center, Toledo, OH 43614, USA
*
Author to whom correspondence should be addressed.
Microorganisms 2025, 13(8), 1859; https://doi.org/10.3390/microorganisms13081859
Submission received: 7 June 2025 / Revised: 30 July 2025 / Accepted: 5 August 2025 / Published: 8 August 2025
(This article belongs to the Special Issue Latest Research in Parasitology: Unlocking Mechanisms, Developing Solutions)
Versions Notes

Abstract

Plasmodium parasites rely on host iron for survival and replication, making host iron availability a critical determinant of malaria pathogenesis. Central to iron homeostasis is the hepcidin–ferroportin regulatory axis, where hepcidin suppresses iron export by inducing ferroportin degradation, thus modulating systemic and cellular iron availability. In the Plasmodium infection model (P. yoelii), we observed a significant downregulation of hepatic hepcidin expression, accompanied by an increase in hepatic ferroportin expression. On the contrary, RBC-ferroportin protein level was notably suppressed upon P. yoelii infection. Given these findings, we aim to investigate the role of a ferroportin inhibitor in Plasmodium infection. In a P. yoelii mouse model, treatment with an oral ferroportin inhibitor, VIT-2763 (Vamifeport) increased parasitemia, accompanied by increased levels of pro-inflammatory cytokines, erythropoietin, and liver injury markers. In P. yoelii infected mice, VIT-2763 treatment suppressed hepcidin expression and increased ferroportin expression in hepatocytes, while reducing ferroportin protein levels in RBCs. VIT-2763 mediated exacerbation of P. yoelii infection reveals the tissue-specific regulation of ferroportin in hepatocytes and RBCs, underscoring the therapeutic potential of modulating the hepcidin–ferroportin axis as an intervention strategy in malaria.
Keywords: P. yoelii; erythropoietin; VIT-2763; vamifeport; reticulocytes; iron homeostasis; malaria; anemia; transferrin; RBC P. yoelii; erythropoietin; VIT-2763; vamifeport; reticulocytes; iron homeostasis; malaria; anemia; transferrin; RBC

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MDPI and ACS Style

Zeydabadinejad, S.; Theis, B.F.; Park, J.S.; Gohara, A.F.; Vijay-Kumar, M.; Yeoh, B.S.; Saha, P. Pharmacologic Inhibition of Erythrocyte Ferroportin Expression Exacerbates Plasmodium Infection. Microorganisms 2025, 13, 1859. https://doi.org/10.3390/microorganisms13081859

AMA Style

Zeydabadinejad S, Theis BF, Park JS, Gohara AF, Vijay-Kumar M, Yeoh BS, Saha P. Pharmacologic Inhibition of Erythrocyte Ferroportin Expression Exacerbates Plasmodium Infection. Microorganisms. 2025; 13(8):1859. https://doi.org/10.3390/microorganisms13081859

Chicago/Turabian Style

Zeydabadinejad, Sareh, Benjamin Frederick Theis, Jun Sung Park, Amira F. Gohara, Matam Vijay-Kumar, Beng San Yeoh, and Piu Saha. 2025. "Pharmacologic Inhibition of Erythrocyte Ferroportin Expression Exacerbates Plasmodium Infection" Microorganisms 13, no. 8: 1859. https://doi.org/10.3390/microorganisms13081859

APA Style

Zeydabadinejad, S., Theis, B. F., Park, J. S., Gohara, A. F., Vijay-Kumar, M., Yeoh, B. S., & Saha, P. (2025). Pharmacologic Inhibition of Erythrocyte Ferroportin Expression Exacerbates Plasmodium Infection. Microorganisms, 13(8), 1859. https://doi.org/10.3390/microorganisms13081859

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