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bioRxiv · 10.1101/2025.10.08.681084

A Plasmodium falciparum molecular mechanism of heme binding and sensitivity to artemisinins

Dutta, S.·Faaiz, M.·Bhattacharjee, S.·Haldar, K.
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Abstract

Mutations in Plasmodium falciparum Kelch13 (K13) confer artemisinin resistance (ART-R) which threatens global malaria control, but known K13 functions fail to explain clinical ART-R. We reported that K13 binds the oxidant heme in vitro, however, its functions in redox-stress, cell survival and death remained unknown. Since taut control of free heme is not feasible in infected erythrocytes, we utilized a non-erythroid cell model to show that K13 directly binds and is stabilized by nanomolar heme levels. K13 also binds and regulates a major redox transcription factor, which is displaced by heme into the nucleus, to raise redox-stress responses that become suppressed during artemisinin-induced death (ART-death). K13s evolutionarily conserved kelch domain confers heme-binding and ART-death characteristics to its mammalian orthologue KEAP1. Chemical or genetic elevation of K13, fuels ART-death proportionate to K13 levels even in vast excess of heme, suggesting a novel plasmodial redox-survival mechanism licenses ART-death in clinical ART-R.

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Dutta, S., Faaiz, M., Bhattacharjee, S., Haldar, K.. 2025-10-08. A Plasmodium falciparum molecular mechanism of heme binding and sensitivity to artemisinins. https://doi.org/10.1101/2025.10.08.681084

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