Fig. 8: Mechanisms by which idelalisib increases sensitivity to ARTs and combats ART resistance. | Communications Biology

Fig. 8: Mechanisms by which idelalisib increases sensitivity to ARTs and combats ART resistance.

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

Fig. 8: Mechanisms by which idelalisib increases sensitivity to ARTs and combats ART resistance.The alternative text for this image may have been generated using AI.

In both ART-sensitive and ART-resistant parasites, idelalisib effectively inhibited PfPI3K activity, resulting in reduced PI3P levels. The reduction in the PI3P level led to the accumulation of ROS produced by activated DHA in P. falciparum. The accumulation of ROS was due to the decreased ROS degradation. Toxic ROS accumulation induced more mitochondrial membrane potential loss, resulting in more DNA fragmentation. Moreover, the reduction in PI3P levels also suppressed the expression of genes encoding molecular chaperones that participate in the UPR pathway, which is responsible for the degradation of damaged proteins induced by ROS in ART-resistant transgenic strains, resulting in the accumulation of ubiquitinated proteins. The accumulation of ubiquitinated proteins also promoted eIF2α phosphorylation, resulting in the persistent of ER stress, leading to disrupted proteostasis in P. falciparum. Overall, the reduction in PI3P by the PfPI3K inhibitor increased the accumulation of ROS as well as the ubiquitinated proteins via the UPR pathway, thereby increasing sensitivity to ARTs and reversing ART resistance. The red arrows represent the mechanism of ART resistance. The green arrows represent the mechanism by which the PfPI3K inhibitor increases sensitivity to ARTs.

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