Abstract

Artemisinin-based combination therapies represented the cornerstone of contemporary malaria treatment, yet 
emerging resistance in Plasmodium falciparum threatens global malaria control achievements. Artemisinin 
resistance manifested as delayed parasite clearance following treatment, driven primarily by mutations in the Kelch 
propeller domain of the K13 gene that confer survival advantages during the early ring stage of parasite 
development. This review examined the molecular mechanisms underlying artemisinin resistance in Plasmodium 
falciparum and evaluated current surveillance strategies for detecting and monitoring resistance emergence and 
spread. A comprehensive synthesis of peer-reviewed literature on K13 mutations, resistance phenotypes, molecular 
surveillance tools, and epidemiological monitoring approaches was conducted. Artemisinin resistance results from 
K13 mutations that alter protein homeostasis pathways, enhancing parasite capacity to withstand oxidative stress 
and maintain cellular quiescence during drug exposure. Validated resistance markers include C580Y and other 
nonsynonymous K13 mutations confirmed through clinical, in vitro, and genetic studies. Molecular surveillance 
utilizing polymerase chain reaction amplification and sequencing of K13 mutations enabled early detection, while 
therapeutic efficacy studies measuring parasite clearance kinetics provided functional resistance assessment. 
Geographic expansion of resistance from Southeast Asia to Africa necessitated intensified surveillance combining 
molecular marker detection, clinical outcome monitoring, and in vitro susceptibility testing. Surveillance gaps 
included limited capacity in resource-constrained settings, delayed reporting systems, and incomplete understanding 
of resistance mechanisms independent of K13 mutations. Integrated surveillance frameworks combining molecular 
diagnostics, clinical monitoring, and standardized reporting are essential for guiding treatment policy and 
containment strategies, though strengthening laboratory capacity and real-time data sharing remained critical 
priorities for effective artemisinin resistance management in malaria-endemic regions.