Targeting Plasmodium falciparum pathways to overcome antimalarial resistance

The global burden of malaria remains substantial, exacerbated by the progressive emergence of resistance to frontline antimalarial therapies. Plasmodium falciparum , the most lethal malaria parasite, has developed reduced susceptibility to artemisinin-based combination therapies and several partner drugs, underscoring the urgent need for therapeutics acting on novel molecular targets. This review aims to critically evaluate emerging molecular targets for antimalarial drug development and assess the current preclinical and clinical evidence supporting their therapeutic potential in overcoming drug resistance. Evidence for this study was gathered through extensive searches of major scientific databases (PubMed, EMBASE, ScienceDirect, SpringerLink, and Google Scholar) from 1985 to 2026. A total of 53 references were selected to support the review. Advances in parasite genomics, metabolic profiling, and high-throughput screening have expanded the antimalarial target landscape, revealing essential enzymes, transporters, and regulatory pathways critical for parasite survival across life cycle stages. The review demonstrates that several genetically validated parasite-specific targets, namely Plasmodium falciparum phosphatidylinositol 4-kinase ( Pf PI4K), the P-type Na ⁺ -ATPase ( Pf ATP4), dihydroorotate dehydrogenase ( Pf DHODH), folate metabolism enzymes, the methylerythritol phosphate (MEP) isoprenoid biosynthesis pathway, and P. falciparum eukaryotic translational elongation factor 2 ( Pf eEF2), have shown promising preclinical and early clinical efficacy. Collectively, these novel pathways represent promising avenues for next-generation antimalarial drug development and combination therapy strategies.