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Based on its cytotoxicity, it is also used for anticancer therapy. Artemisinin and its derivates are endoperoxides that damage proteins in eukaryotic cells; their definite mechanism of action and host cell targets, however, have remained largely elusive. Using yeast and haploid stem cell screening, we demonstrate that a single cellular pathway, namely porphyrin (heme) biosynthesis, is required for the cytotoxicity of Artemisinins. Genetic or pharmacological modulation of porphyrin production is sufficient to alter its cytotoxicity in eukaryotic cells. Using multiple model systems of human brain tumor development, such as cerebral glioblastoma organoids, and patient\u2010derived tumor spheroids, we sensitize cancer cells to dihydroartemisinin using the clinically approved porphyrin enhancer and surgical fluorescence marker 5\u2010aminolevulinic acid, 5\u2010ALA. A combination treatment of Artemisinins and 5\u2010ALA markedly and specifically killed brain tumor cells in all model systems tested, including orthotopic patient\u2010derived xenografts\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    . These data uncover the critical molecular pathway for Artemisinin cytotoxicity and a sensitization strategy to treat different brain tumors, including drug\u2010resistant human glioblastomas.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202216959","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T03:23:01Z","timestamp":1675653781000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A whole\u2010genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3377-2026","authenticated-orcid":false,"given":"Jasmin","family":"Taubenschmid\u2010Stowers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Orthofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Laemmerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Krauditsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"R\u00f3zsov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4802-0225","authenticated-orcid":false,"given":"Christian","family":"Studer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"L\u00f6tsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Gojo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Gabler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matheus","family":"Dyczynski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Efferth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3015-4038","authenticated-orcid":false,"given":"Astrid","family":"Hagelkruys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Widhalm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5736-8231","authenticated-orcid":false,"given":"Andreas","family":"Peyrl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Spiegl\u2010Kreinecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic","family":"Hoepfner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4507-3003","authenticated-orcid":false,"given":"Shan","family":"Bian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6751-3404","authenticated-orcid":false,"given":"Juergen A","family":"Knoblich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Elling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Horn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8194-3777","authenticated-orcid":false,"given":"Josef M","family":"Penninger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"key":"BFEMMM202216959_CR1","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1093\/jac\/dkt486","volume":"69","author":"T Antoine","year":"2014","unstructured":"Antoine T, Fisher N, Amewu R, O'Neill PM, Ward SA, Biagini GA (2014) Rapid kill of malaria parasites by artemisinin and semi\u2010synthetic endoperoxides involves ROS\u2010dependent depolarization of the membrane potential. 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