Spermidine is a key polyamine required by intracellular parasites for survival within host erythrocytes.

Intracellular parasites, including Babesia and Plasmodium, the agents of human babesiosis and malaria, depend on the salvage or de novo synthesis of critical nutrients for survival within human erythrocytes. Among these, polyamines play a pivotal role, but their specific requirements and molecular functions in intraerythrocytic parasites remain poorly understood. We identify spermidine as a key polyamine for Babesia duncani and Plasmodium falciparum for intraerythrocytic development. We demonstrate that spermidine is indispensable for regulating protein translation through hypusination of the eukaryotic translation initiation factor eIF5A, and its depletion leads to increased production of reactive oxygen species. Disruption of spermidine biosynthesis or its conversion from spermine results in parasite death. We also show that B. duncani and other Babesia species use an ancestral spermidine synthase-like enzyme, highlighting a distinct evolutionary adaptation from P. falciparum. Our results reveal the spermidine's dual role in oxidative stress defense and translation regulation, positioning spermidine biosynthesis as a critical vulnerability and a promising therapeutic target.