Epigenetically conferred ring-stage survival in Plasmodium falciparum against artemisinin treatment

Xinyu Yu, Jincan He, Changhong Wang, Jianbing Mu, Xuan Chen, Yuemeng Zhao, Xiaohui He, Sihong Liu, Juliana M. Sa, Lucien Platon, Jianxia Tang, Wenwen Si, Ruoyu Tang, Didier Menard (), Thomas E. Wellems (), Cizhong Jiang (), Jun Cao () and Qingfeng Zhang ()
Additional contact information
Xinyu Yu: Tongji University
Jincan He: Tongji University
Changhong Wang: Tongji University
Jianbing Mu: National Institutes of Health
Xuan Chen: Nanchang Medical College
Yuemeng Zhao: Tongji University
Xiaohui He: Jiangsu Institute of Parasitic Diseases
Sihong Liu: Jiangsu Institute of Parasitic Diseases
Juliana M. Sa: National Institutes of Health
Lucien Platon: Université de Strasbourg
Jianxia Tang: Jiangsu Institute of Parasitic Diseases
Wenwen Si: Tongji University
Ruoyu Tang: Tongji University
Didier Menard: Université de Strasbourg
Thomas E. Wellems: National Institutes of Health
Cizhong Jiang: Tongji University
Jun Cao: Jiangsu Institute of Parasitic Diseases
Qingfeng Zhang: Tongji University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Artemisinin and its semisynthetic derivatives (ART) are crucial medicines in artemisinin-based combination therapies worldwide. Despite ART’s efficacy, small proportions of young intraerythrocytic ring stage parasites can survive the drug’s short half-life, and dormant forms can cause recrudescence if not cleared by partner drugs. Certain mutations in the Kelch propeller region of P. falciparum protein (PfK13) are linked to the higher ring-stage survival (RS), which above 1% can be a feature of ‘artemisinin partial resistance’. Emerging evidence indicates epigenetic modulators may contribute to RS. Here, we report systematic evaluations of all putative histone acetyltransferases (HATs) of P. falciparum in 30 culture-adapted field isolates and 43 subcloned field isolates. Only PfMYST shows a full association with RS phenotype modulations. Knockdown experiments confirm the linkage of Pfmyst expression to these modulations, with evidence of altered metabolic processes. Through single-cell RNA sequencing, ChIP-seq analysis, and CRISPR/cas9 genetic manipulation, PfMYST-targeted RS-related genes have been identified and functionally validated. Multi-omics analysis indicates significant interplay of PfMYST and PfK13 mechanisms in RS. PfMYST epigenetic modulation extends to other antimalarials, including amodiaquine, pyrimethamine, chloroquine, and pyronaridine. Collectively, our findings provide important information on the epigenetic regulatory mechanism of P. falciparum RS after pulses of ART and other antimalarials.

Date: 2025
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DOI: 10.1038/s41467-025-62479-2

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