Targeting Iron Homeostasis Curtails Mosquito Fertility and Plasmodium Transmission Potential

Iron metabolism is essential for both mosquito reproductive fitness and Plasmodium development within the mosquito, yet this axis has remained insufficiently explored as a potential target for malaria control. Ferritin, the major iron-storage protein and a central regulator of iron homeostasis, has not been biochemically or functionally characterized in any hematophagous insect to date. Our computational and phylogenetic analyses reveal that mosquito ferritin represents a unique case, exhibiting a chimeric architecture that combines conserved iron-binding motifs with distinctive heme-coordinating residues, resulting in an exceptionally high heme-binding affinity that surpasses that of bacterioferritin. Functional knockdown of the ferritin heavy-chain subunit in adult Anopheles stephensi females caused profound defects in reproductive tissue development, confirming its essential role in mosquito physiology, iron storage, and transport. Furthermore, capitalizing on the host–parasite competition for iron, we screened multiple chelators and identified β-thujaplicin as a potent transmission-blocking agent that significantly suppressed Plasmodium oocyst development. Together, these findings establish mosquito ferritin as an evolutionarily distinct, physiologically essential protein and position iron homeostasis as a powerful dual-target axis for next-generation transmission-blocking interventions.