Host iron deficiency protects against <i>Plasmodium</i> infection and drives parasite molecular reprofiling

Iron deficiency, anemia, and <i>Plasmodium</i> 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 (<i>n</i> = 711) in the REVAMP trial, a genetic mouse model [<i>Tmprss6</i>-knockout (KO)], and in vitro <i>Plasmodium falciparum</i> cultures to clarify iron-malaria associations. Iron deficiency was associated with 50% reduced <i>P. falciparum</i> parasitemia in pregnant women [95% CI (30 to 64%), <i>P</i> < 0.0001], while iron-deficient mice exhibited improved survival against <i>P. berghei</i> (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 <i>P. falciparum</i> parasites. Intravenous iron supplementation did not increase parasitemia when coupled with malaria prevention. These findings demonstrate that iron deficiency protects against <i>Plasmodium</i> infection and support World Health Organization recommendations for iron supplementation in malaria-endemic regions when combined with adequate malaria prevention strategies in place.