Cellular and molecular basis of PfCoronin function in artemisinin resistance in Plasmodium falciparum.

Artemisinin combination therapies are central to malaria control, but their efficacy is threatened by the emergence of resistant Plasmodium falciparum strains. While the role of Pfkelch13 mutations is well established, mutations in Pfcoronin have also been implicated in treatment failure, revealing layers of resistance complexity. Here, we define the cellular mechanism of Pfcoronin‑mediated artemisinin resistance. PfCoronin interacts with PfActin and localizes to the parasite plasma membrane, the digestive vacuole membrane, and small vesicles containing host cell material. Mutations in PfCoronin disrupt its localization and perturb PfActin homeostasis, altering the distribution of ring‑stage morphologies, including a reduced proportion of parasites adopting the cup‑shaped architecture. These changes are associated with decreased uptake of host cell contents by ring‑stage P. falciparum. Consistent with prior work on Pfkelch13 mutants, reduced hemoglobin uptake emerges as a feature of Pfcoronin‑mediated resistance. Although PfKelch13 and PfCoronin reside in distinct compartments and show no evidence of direct interaction, both influence endocytic access to hemoglobin. We propose that reduced hemoglobin uptake in ring‑stage parasites limits heme‑dependent activation of artemisinin and thus reduces its cytocidal activity. Our findings demonstrate that Pfcoronin mutations reduce endocytosis and modulate artemisinin susceptibility-highlighting how non‑essential, temporally restricted proteins can shape drug response and resistance.