The many paths to artemisinin resistance in Plasmodium falciparum

Emerging resistance against artemisinin (ART) poses a major challenge in con-trolling malaria. Parasites with mutations in PfKelch1 3, the major marker for ART resistance, are known to reduce hemoglobin endocytosis, induce unfolded protein response (UPR), elevate phosphatidylinositol-3-phosphate (PI3P) levels, and stimulate autophagy. Nonetheless, PfKelch13-independent resis-tance is also reported, indicating extensive complementation by reconfigura-tion in the parasite metabolome and transcriptome. These findings implicate that there may not be a single 'universal identifier' of ART resistance. This review sheds light on the molecular, transcriptional, and metabolic pathways associated with ART resistance, while also highlighting the interplay between cellular hetero-geneity, environmental stress, and ART sensitivity.