PfPI3K inhibition reversed artemisinin resistance by increasing ROS and ubiquitinated protein levels in Plasmodium falciparum

Phosphatidylinositol-3-phosphate (PI3P) is the key mediator of resistance to artemisinin drugs (ARTs) and that phosphatidylinositol 3-kinase (PfPI3K) is a promising target for eliminating ARTs resistance. However, few studies investigated the PfPI3K inhibitors. Here we show combination treatment with a potential PfPI3K inhibitor (idelalisib, which effectively inhibit PfPI3K activity resulting the decline in PI3P level) and dihydroartemisinin (DHA) exerts synergistic antimalarial effects and reverse ARTs resistance. The decline in PI3P level inhibits reactive oxygen species (ROS) degradation (resulting in ROS accumulation, apoptosis of parasites and the accumulation of ubiquitinated proteins), downregulates the gene expression of molecular chaperones and increases eIF2α phosphorylation, which finally leads to a dysregulated antioxidant system and disrupted proteostasis in parasites, thereby increasing the sensitivity of the parasites to ARTs and reversing ARTs resistance. Our results indicated that targeting PfPI3K with idelalisib was a successful antimalarial strategy for further controlling the development of ART resistance.