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We present an overview of the genetic loci that, in mutant form, can independently elicit parasite tolerance. These encode Kelch propeller domain protein PfK13, ubiquitin hydrolase UBP-1, actin filament-organising protein Coronin, also carrying a propeller domain, and the trafficking adaptor subunit AP-2\u03bc. Detailed studies of these proteins and the functional basis of artemisinin tolerance in blood-stage parasites are enabling a new synthesis of our understanding to date. To guide further experimental work, we present two major conclusions. First, we propose a dual-component model of artemisinin tolerance in P. falciparum comprising suppression of artemisinin activation in early ring stage by reducing endocytic haemoglobin capture from host cytosol, coupled with enhancement of cellular healing mechanisms in surviving cells. Second, these two independent requirements limit the likelihood of development of complete artemisinin resistance by P. falciparum, favouring deployment of existing drugs in new schedules designed to exploit these biological limits, thus extending the useful life of current combination therapies.<\/jats:p>","DOI":"10.1093\/femsre\/fuaa056","type":"journal-article","created":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T11:21:18Z","timestamp":1603279278000},"source":"Crossref","is-referenced-by-count":40,"title":["Artemisinin susceptibility in the malaria parasite<i>Plasmodium falciparum<\/i>: propellers, adaptor proteins and the need for cellular healing"],"prefix":"10.1093","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-6407","authenticated-orcid":false,"given":"Colin J","family":"Sutherland","sequence":"first","affiliation":[{"name":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan C","family":"Henrici","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK"},{"name":"Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Artavanis-Tsakonas","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Cambridge, Tennis Court Rd, Cambridge CB2 1QP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,10,23]]},"reference":[{"key":"2021050613063511800_bib1","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1242\/jcs.061499","article-title":"Digestive-vacuole genesis and 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