Host iron deficiency protects against Plasmodium infection and drives parasite molecular reprofiling.

Iron deficiency, anemia, and Plasmodium infection are global health challenges with overlapping geographical distributions, particularly affecting pregnant women in Africa, yet the mechanisms underlying their interactions remain poorly understood. We used a multilayered approach combining clinical data from Malawian pregnant women (n = 711) in the REVAMP trial, a genetic mouse model [Tmprss6-knockout (KO)], and in vitro Plasmodium falciparum cultures to clarify iron-malaria associations. Iron deficiency was associated with 50% reduced P. falciparum parasitemia in pregnant women [95% CI (30 to 64%), P < 0.0001], while iron-deficient mice exhibited improved survival against P. berghei (median 15.5 days versus 7.0 days for WT mice) and protection from cerebral malaria (83% versus 17% survival). Iron chelation substantially changed the transcriptomic and proteomic profile of cultured P. falciparum parasites. Intravenous iron supplementation did not increase parasitemia when coupled with malaria prevention. These findings demonstrate that iron deficiency protects against Plasmodium infection and support World Health Organization recommendations for iron supplementation in malaria-endemic regions when combined with adequate malaria prevention strategies in place.