Pharmacologic Inhibition of Erythrocyte Ferroportin Expression Exacerbates Plasmodium Infection

<i>Plasmodium</i> 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 <i>Plasmodium</i> infection model (<i>P. yoelii</i>), we observed a significant downregulation of hepatic <i>hepcidin</i> expression, accompanied by an increase in hepatic <i>ferroportin</i> expression. On the contrary, RBC-ferroportin protein level was notably suppressed upon <i>P. yoelii</i> infection. Given these findings, we aim to investigate the role of a ferroportin inhibitor in <i>Plasmodium</i> infection. In a <i>P. yoelii</i> 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 <i>P. yoelii</i> infected mice, VIT-2763 treatment suppressed <i>hepcidin</i> expression and increased <i>ferroportin</i> expression in hepatocytes, while reducing ferroportin protein levels in RBCs. VIT-2763 mediated exacerbation of <i>P. yoelii</i> 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.