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Artemisinin, the cornerstone of artemisinin-based combination therapies, is the most potent drug in the antimalarial armamentarium against falciparum malaria. Heme-mediated activation of artemisinin and its derivatives results in widespread parasite protein alkylation, which is thought to lead to parasite death. Alarmingly, cases of decreased artemisinin efficacy have been widely detected across Cambodia and in neighboring countries, and a few cases have been reported in the Guiana Shield, India, and Africa. The grim prospect of widespread artemisinin resistance propelled a concerted effort to understand the mechanisms of artemisinin action and resistance. The identification of genetic markers and the knowledge of molecular mechanisms underpinning artemisinin resistance allow prospective surveillance and inform future drug development strategies, respectively. Here, we highlight recent advances in our understanding of how parasite vesicle trafficking, hemoglobin digestion, and cell stress responses contribute to artemisinin resistance.<\/jats:p>","DOI":"10.1021\/acsinfecdis.9b00527","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T16:54:41Z","timestamp":1587660881000},"page":"1599-1614","source":"Crossref","is-referenced-by-count":68,"title":["<i>Plasmodium falciparum<\/i>\n                    Artemisinin\nResistance: The Effect of Heme, Protein Damage, and Parasite Cell\nStress Response"],"prefix":"10.1021","volume":"6","author":[{"given":"Melissa R.","family":"Rosenthal","sequence":"first","affiliation":[{"name":"University of Nebraska Medical Center , , , ,","place":["Omaha, Nebraska, United States, 68198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8267-8453","authenticated-orcid":true,"given":"Caroline L.","family":"Ng","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center , , , ,","place":["Omaha, Nebraska, United States, 68198"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,4,23]]},"reference":[{"key":"2026081722193298600_cit1","unstructured":"WHO\n          . (2019) in World Malaria Report 2019, World Health Organization. https:\/\/www.who.int\/publications-detail\/world-malaria-report-2019."},{"issue":"7","key":"2026081722193298600_cit2","doi-asserted-by":"publisher","first-page":"3268","DOI":"10.1128\/AAC.00325-13","article-title":"Male and female Plasmodium\nfalciparum mature gametocytes show different responses to\nantimalarial drugs","volume":"57","author":"Delves","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"issue":"1","key":"2026081722193298600_cit3","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1021\/cb300454t","article-title":"Insights into the\nrole of heme in the mechanism of action of antimalarials","volume":"8","author":"Combrinck","year":"2013","journal-title":"ACS Chem. Biol."},{"issue":"10","key":"2026081722193298600_cit4","doi-asserted-by":"publisher","first-page":"3768","DOI":"10.1128\/AAC.00239-07","article-title":"Trioxaquines and heme-artemisinin adducts inhibit the\nin vitro formation of hemozoin better than chloroquine","volume":"51","author":"Loup","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"issue":"28","key":"2026081722193298600_cit5","doi-asserted-by":"publisher","first-page":"11405","DOI":"10.1073\/pnas.1104063108","article-title":"Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion","volume":"108","author":"Klonis","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"1","key":"2026081722193298600_cit6","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1128\/AAC.03663-14","article-title":"Antimalarial action\nof artesunate involves DNA damage mediated by reactive oxygen species","volume":"59","author":"Gopalakrishnan","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081722193298600_cit7","doi-asserted-by":"publisher","first-page":"10111","DOI":"10.1038\/ncomms10111","article-title":"Haem-activated promiscuous targeting of artemisinin in Plasmodium\nfalciparum","volume":"6","author":"Wang","year":"2015","journal-title":"Nat. Commun."},{"issue":"8","key":"2026081722193298600_cit8","doi-asserted-by":"publisher","first-page":"2080","DOI":"10.1073\/pnas.1600459113","article-title":"Artemisinin activity-based\nprobes identify multiple molecular targets within the asexual stage\nof the malaria parasites Plasmodium falciparum 3D7","volume":"113","author":"Ismail","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"12","key":"2026081722193298600_cit9","doi-asserted-by":"publisher","first-page":"2067","DOI":"10.1021\/acsinfecdis.9b00264","article-title":"Stochastic\nprotein alkylation by antimalarial peroxides","volume":"5","author":"Jourdan","year":"2019","journal-title":"ACS Infect. Dis."},{"issue":"1","key":"2026081722193298600_cit10","doi-asserted-by":"publisher","first-page":"3801","DOI":"10.1038\/s41467-018-06221-1","article-title":"Artemisinin kills malaria parasites by damaging proteins\nand inhibiting the proteasome","volume":"9","author":"Bridgford","year":"2018","journal-title":"Nat. Commun."},{"issue":"6","key":"2026081722193298600_cit11","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.1016\/j.bbagen.2014.02.009","article-title":"Malarial hemozoin: from target to\ntool","volume":"1840","author":"Coronado","year":"2014","journal-title":"Biochim. Biophys. Acta, Gen. Subj."},{"key":"2026081722193298600_cit12","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1146\/annurev.micro.51.1.97","article-title":"Hemoglobin metabolism\nin the malaria parasite Plasmodium falciparum","volume":"51","author":"Francis","year":"1997","journal-title":"Annu. Rev. Microbiol."},{"issue":"13","key":"2026081722193298600_cit13","doi-asserted-by":"publisher","first-page":"5157","DOI":"10.1073\/pnas.1217452110","article-title":"Altered temporal response\nof malaria parasites determines differential sensitivity to artemisinin","volume":"110","author":"Klonis","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. 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Agents Chemother."},{"issue":"16","key":"2026081722193298600_cit16","doi-asserted-by":"publisher","first-page":"7853","DOI":"10.1016\/j.bmc.2008.02.034","article-title":"Heme activates artemisinin more efficiently than hemin,\ninorganic iron, or hemoglobin","volume":"16","author":"Zhang","year":"2008","journal-title":"Bioorg. Med.\nChem."},{"issue":"2","key":"2026081722193298600_cit17","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1242\/jcs.178830","article-title":"Haemoglobin\ndegradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins","volume":"129","author":"Xie","year":"2016","journal-title":"J. Cell Sci."},{"issue":"11","key":"2026081722193298600_cit18","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1021\/ar100070k","article-title":"Heme as trigger and target for trioxane-containing\nantimalarial drugs","volume":"43","author":"Meunier","year":"2010","journal-title":"Acc. Chem. 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J."},{"issue":"1","key":"2026081722193298600_cit27","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1186\/s12936-017-1983-9","article-title":"Clinical\nand molecular surveillance of artemisinin resistant falciparum malaria\nin Myanmar (2009\u20132013)","volume":"16","author":"Nyunt","year":"2017","journal-title":"Malar. J."},{"issue":"10","key":"2026081722193298600_cit28","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1056\/NEJMc1612765","article-title":"Emergence of indigenous\nartemisinin-resistant Plasmodium falciparum in Africa","volume":"376","author":"Lu","year":"2017","journal-title":"N. Engl. J. Med."},{"issue":"7","key":"2026081722193298600_cit29","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.3201\/eid2107.150213","article-title":"Slow clearance of Plasmodium falciparum in severe pediatric malaria, Uganda, 2011\u20132013","volume":"21","author":"Hawkes","year":"2015","journal-title":"Emerging Infect. Dis."},{"issue":"6","key":"2026081722193298600_cit30","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1016\/j.ijantimicag.2017.01.032","article-title":"Absence of association between polymorphisms\nin the K13 gene and the presence of Plasmodium falciparum parasites at day 3 after treatment with artemisinin derivatives\nin Senegal","volume":"49","author":"Madamet","year":"2017","journal-title":"Int. J. Antimicrob. Agents"},{"issue":"20","key":"2026081722193298600_cit31","doi-asserted-by":"publisher","first-page":"1962","DOI":"10.1056\/NEJMc1713777","article-title":"Evidence of artemisinin-resistant Plasmodium falciparum malaria in eastern India","volume":"379","author":"Das","year":"2018","journal-title":"N. Engl. J. Med."},{"issue":"8","key":"2026081722193298600_cit32","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1590\/0074-0276130167","article-title":"Evidence of an increased incidence of day 3 parasitaemia\nin Suriname: an indicator of the emerging resistance of Plasmodium\nfalciparum to artemether","volume":"108","author":"Vreden","year":"2013","journal-title":"Mem Inst\nOswaldo Cruz"},{"issue":"1","key":"2026081722193298600_cit33","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1093\/jac\/dkx343","article-title":"Predictors of antimalarial self-medication in illegal\ngold miners in French Guiana: a pathway towards artemisinin resistance","volume":"73","author":"Douine","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"issue":"12","key":"2026081722193298600_cit34","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/S1473-3099(13)70252-4","article-title":"Novel phenotypic assays\nfor the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies","volume":"13","author":"Witkowski","year":"2013","journal-title":"Lancet Infect. Dis."},{"issue":"7481","key":"2026081722193298600_cit35","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature12876","article-title":"A molecular marker\nof artemisinin-resistant Plasmodium falciparum malaria","volume":"505","author":"Ariey","year":"2014","journal-title":"Nature"},{"issue":"6220","key":"2026081722193298600_cit36","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1126\/science.1260867","article-title":"K13-propeller mutations confer artemisinin\nresistance in Plasmodium falciparum clinical isolates","volume":"347","author":"Straimer","year":"2015","journal-title":"Science"},{"issue":"5","key":"2026081722193298600_cit37","doi-asserted-by":"publisher","first-page":"1872","DOI":"10.1128\/AAC.01636-09","article-title":"Increased\ntolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism","volume":"54","author":"Witkowski","year":"2010","journal-title":"Antimicrob.\nAgents Chemother."},{"issue":"1","key":"2026081722193298600_cit38","doi-asserted-by":"publisher","first-page":"10675","DOI":"10.1038\/s41598-019-47034-6","article-title":"Comparative structural and evolutionary\nanalyses predict functional sites in the artemisinin resistance malaria\nprotein K13","volume":"9","author":"Coppee","year":"2019","journal-title":"Sci. Rep."},{"issue":"1","key":"2026081722193298600_cit39","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1186\/s12936-017-2128-x","article-title":"Plasmodium falciparum Kelch 13 mutations and treatment response in patients in Hpa-Pun\nDistrict, Northern Kayin State, Myanmar","volume":"16","author":"Bonnington","year":"2017","journal-title":"Malar.\nJ."},{"issue":"25","key":"2026081722193298600_cit40","doi-asserted-by":"publisher","first-page":"2453","DOI":"10.1056\/NEJMoa1513137","article-title":"A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms","volume":"374","author":"Menard","year":"2016","journal-title":"N. Engl. J. Med."},{"issue":"1","key":"2026081722193298600_cit41","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1093\/molbev\/msw228","article-title":"Population parameters\nunderlying an ongoing soft sweep in Southeast Asian malaria parasites","volume":"34","author":"Anderson","year":"2017","journal-title":"Mol. Biol. 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Infect.\nDis."},{"issue":"49","key":"2026081722193298600_cit46","doi-asserted-by":"publisher","first-page":"12513","DOI":"10.1073\/pnas.1813386115","article-title":"Artemisinin resistance phenotypes\nand K13 inheritance in a Plasmodium falciparum cross\nand Aotus model","volume":"115","author":"Sa","year":"2018","journal-title":"Proc. Natl.\nAcad. Sci. U. S. 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