<scp>HIF</scp> ‐1α/ <scp>HMOX1</scp> ‐Mediated Ferroptosis in Macrophages Exacerbates Malaria Progression

ABSTRACT The spleen orchestrates anti‐malarial immunity, with its macrophages phagocytizing Plasmodium ‐infected blood cells (iRBCs). While regulated cell death (RCD) has been extensively studied in various diseases, the relationship between regulatory cell death of splenic macrophages and the progression of malaria infection remains unexplored. In this study, we identify that Plasmodium infection triggers ferroptosis in splenic macrophages characterized by aberrant HMOX1 upregulation concomitant with HIF‐1α downregulation. Mechanistically, the loss of HIF‐1α signaling fails to restrain HMOX1 expression, leading to Fe 2+ overload. Fer‐1 inhibits ferroptosis in iRBC‐exposed macrophages in vitro. P. yoelii ‐infected mice show elevated ferroptosis biomarkers in splenic macrophages, reversible by Fer‐1 treatment. Additionally, compared to GPX4 flox/flox infected mice, the conditional knockout infected mice ( GPX4 flox/flox Lyz2 Cre + ) display worsened health conditions and more severe parasitemia. Moreover, identical ferroptosis signature is detected in monocytes from malaria patient PBMCs, confirming cross‐species conservation. In conclusion, these findings suggest that Plasmodium yoelii NSM infection triggers ferroptosis in splenic macrophages, which exacerbates malaria progression. Targeting the HIF‐1α/HMOX1 axis to modulate macrophage ferroptosis alleviates the progression of Plasmodium infection, providing crucial mechanistic insights that warrant cautious exploration for host‐directed interventions.