Why not now? Targeting Plasmodium falciparum histone methyltransferases for next-generation antimalarial strategies.

Plasmodium falciparum is the major human malaria parasite and its treatment remains challenging, with current artemisinin-based combination therapies increasingly compromised by emerging resistance in several regions. Although the pre-erythrocytic vaccines, Mosquirix and R21, are recommended only for children under five years of age in highly endemic African regions, their protective efficacy is moderate and wanes over time, underscoring the continued need for effective antimalarial drugs. Epigenetic mechanisms play a central role in regulating the parasite genome in response to diverse host environments, with methyltransferases acting as key components that dynamically modulate chromatin structure to control stage-specific gene expression. These epigenetic factors critically shape parasite fate by governing the expression of surface antigens, including var, RIFINs and STEVORs, thereby enabling immune evasion and the establishment of chronic infections. To date, no therapeutics specifically targeting histone lysine methyltransferases (HKMTs) have reached clinical use, although BIX-01294 has been explored as a candidate antimalarial in preclinical studies. This review synthesizes current knowledge on Plasmodium HKMTs, highlighting their biochemical activities, regulatory roles, and contributions to virulence. While evaluating emerging epigenetic inhibitors as potential antimalarial agents. We further discuss the main challenges in developing such therapies, emphasizing the necessity of detailed structural characterization, optimized pharmacological properties and rigorous validation of candidate compounds across Plasmodium species to enable successful translation.