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In mammalian cells, the small-molecule compound RAS-selective lethal 3 (RSL3) induces ferroptosis via lipid peroxidation. In this study, we demonstrate that RSL3 synergizes with Pyrimethamine, an inhibitor of\n                      <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                      dihydrofolate reductase (DHFR), to suppress parasite proliferation in red blood cells (RBCs). A similar synergistic effect was observed with Cycloguanil, a structural analog of Pyrimethamine, but not with other DHFR inhibitors or alternative agents that induce ferroptosis in nucleated mammalian cells. Notably, Ferrostatin-1, an antagonist of lipid peroxidation, largely failed to rescue parasite growth in the presence of RSL3, possibly suggesting a mechanism distinct from canonical ferroptosis. These findings suggest that the synergy may involve unidentified targets of RSL3 and Pyrimethamine in\n                      <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                      , divergent from those described in mammalian systems. Moreover, RSL3 and related compounds could serve as promising adjuvants to enhance the antimalarial efficacy of Pyrimethamine and potentially overcome drug resistance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00471-25","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T12:00:38Z","timestamp":1755518438000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Synergistic activity of RSL3 and Pyrimethamine to inhibit the proliferation of\n                    <i>Plasmodium falciparum<\/i>"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1334-3008","authenticated-orcid":false,"given":"Vella","family":"Nikolova","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/021ft0n22","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Oncology, G\u00f6ttingen Center of Molecular Biosciences (GZMB), University Medical Center G\u00f6ttingen","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Linnemannst\u00f6ns","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/021ft0n22","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Oncology, G\u00f6ttingen Center of Molecular Biosciences (GZMB), University Medical Center G\u00f6ttingen","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiia","family":"Zahoruiko","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/021ft0n22","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Oncology, G\u00f6ttingen Center of Molecular Biosciences (GZMB), University Medical Center G\u00f6ttingen","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0684-2260","authenticated-orcid":true,"given":"Markus","family":"Ganter","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/038t36y30","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Diseases \u2013 Parasitology, Medical Faculty, Heidelberg University","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6228-6356","authenticated-orcid":true,"given":"Carsten G.","family":"L\u00fcder","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/021ft0n22","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Medical Microbiology and Virology, University Medical Center G\u00f6ttingen","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5052-3967","authenticated-orcid":true,"given":"Matthias","family":"Dobbelstein","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/021ft0n22","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Oncology, G\u00f6ttingen Center of Molecular Biosciences (GZMB), University Medical Center G\u00f6ttingen","place":["G\u00f6ttingen, Germany"]},{"id":[{"id":"https:\/\/ror.org\/03av75f26","id-type":"ROR","asserted-by":"publisher"}],"name":"Max Planck Institute for Multidisciplinary Sciences","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.50"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60024-0"},{"key":"e_1_3_3_4_2","volume-title":"World malaria report 2024: addressing inequity in the global malaria response","author":"WHO","year":"2024","unstructured":"WHO. 2024. 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