Abstract

Artemisinin-based combination therapies (ACTs) represent the cornerstone of contemporary falciparum malaria 
treatment worldwide. However, the emergence and spread of artemisinin-resistant Plasmodium falciparum strains 
pose significant threats to global malaria elimination efforts. This review examines current understanding of 
artemisinin resistance mechanisms in P. falciparum, focusing on molecular pathways, biomarkers, and clinical 
implications for therapeutic management. A comprehensive literature search was conducted using PubMed, Scopus, 
and Web of Science databases (2012-2025), with emphasis on peer-reviewed studies examining Kelch13 mutations, 
resistance mechanisms, and clinical outcomes. Artemisinin resistance primarily involves mutations in the Kelch13 
(K13) protein, particularly in the propeller domain, leading to reduced hemoglobin endocytosis and altered parasite 
stress responses. The most prevalent resistance-conferring mutations include C580Y, R539T, and Y493H, which 
demonstrate variable geographic distribution and fitness costs. Resistance mechanisms encompass disrupted 
endocytic pathways, enhanced unfolded protein response activation, and modified phosphatidylinositol 3-phosphate 
signaling. Clinical manifestations include delayed parasite clearance times, with clearance half-life (t1/2) values 
exceeding 5 hours, indicating resistance. Understanding artemisinin resistance mechanisms is crucial for developing 
next-generation antimalarials and optimizing current therapeutic strategies. Continued molecular surveillance and 
development of alternative therapeutic approaches remain paramount for sustaining malaria control achievements.