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bioRxiv · 10.1101/2025.08.28.672746

Epitranscriptomic Dysregulation Underpins Artemisinin Mechanism of Action

Sinha, A.·Lee, B. S. T.·Kwah, J. S.·Liang, J.·Murray, H.·Omelianczyk, R. I.·Baumbarten, S.·Dedon, P. C.·Preiser, P.
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Abstract

Artemisinin has long been a first-line antimalarial. Yet, its mode of action is still poorly understood. Emergence of artemisinin-resistant strains highlight the importance of addressing this question so as to develop better drugs and overcome resistance. In this study, we performed RNA-sequencing and proteomics studies on artemisinin treated parasites indicated a striking difference in the codon-usage pattern of differentially translated genes. Using a liquid chromatography-coupled mass spectrometry (LC-MS)-based platform, we have quantified the full spectrum of modified ribonucleosides on tRNA in P. falciparum in response to the drug. We found that N6-threonyl-carbomyladenosine (t6A), a universal tRNA modification found at position 37 is hypomodified in response to artemisinin induced stress. Additionally, we also found that artemisinin treatment resulted in a downregulation of PfSua5, an enzyme involved in the t6A biosynthesis machinery. These findings provide new insights into how artemisinin works. More broadly, the findings exposes the tRNA epitranscriptome as a vulnerability in the parasite that can be exploited for new drugs.

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Sinha, A., Lee, B. S. T., Kwah, J. S., Liang, J., Murray, H., Omelianczyk, R. I., Baumbarten, S., Dedon, P. C., Preiser, P.. 2025-08-28. Epitranscriptomic Dysregulation Underpins Artemisinin Mechanism of Action. https://doi.org/10.1101/2025.08.28.672746

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