Abstract

Malaria remained a major global health challenge, with Plasmodium falciparum responsible for the most severe and 
fatal forms of the disease. Artemisinin-based combination therapy has been the cornerstone of P. falciparum malaria 
treatment for over two decades due to its rapid parasite clearance and high clinical efficacy. However, the emergence 
and spread of artemisinin resistance threatened recent gains in malaria control and elimination. The purpose of this 
review was to examine the biochemical and molecular mechanisms underlying artemisinin resistance in P. falciparum 
and to evaluate treatment outcomes associated with artemisinin-based combination therapy in both resistant and 
non-resistant settings. This article was developed through a critical narrative review of published experimental, 
molecular, and clinical studies on artemisinin pharmacology, resistance markers, and therapeutic outcomes. Current 
evidence indicates that resistance is mediated primarily through mutations in the kelch13 gene, altered parasite 
stress responses, and changes in hemoglobin metabolism, leading to delayed parasite clearance. Despite these 
challenges, artemisinin-based combination therapy continued to demonstrate high cure rates in most endemic 
regions, although declining efficacy has been reported in parts of Southeast Asia, and emerging signals are being 
observed in Africa. Sustained surveillance, molecular monitoring, and the development of novel combination 
strategies were essential to preserve the clinical effectiveness of artemisinin-based therapies and support global 
malaria elimination efforts.