Fifty shades of iron: Unorthodox mechanisms of iron acquisition and utilization in blood-stage Plasmodium parasites

Plasmodium falciparum parasites cause severe human malaria and depend on iron for essential metabolic processes during all phases of their complicated lifecycle, including when growing in human red blood cells (RBCs). Despite decades of study, the major pathways by which malaria parasites access, distribute, and regulate iron during blood-stage infection remain incompletely defined. The parasite genome lacks many canonical transporters, storage proteins, reductases, and regulatory circuits that are essential for maintaining iron homeostasis in model organisms. Emerging evidence suggests that blood-stage parasites employ unconventional strategies to maintain iron homeostasis. In this review, we synthesize current knowledge of how blood-stage P. falciparum manages iron, from initial uptake through cellular distribution to utilization, highlighting the key proteins and pathways that shape parasite iron metabolism. We also identify major unanswered questions that will guide future efforts to understand and therapeutically target this essential aspect of Plasmodium biology.