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Therapeutic strategies that address both metabolic and inflammatory balances are thus required. Itaconate, a metabolite produced by aconitate decarboxylase 1 (ACOD1), is a potent inhibitor of both inflammation and glycolysis with protective effects in various inflammatory diseases. Although elevated itaconate levels have been observed in <jats:italic>Plasmodium<\/jats:italic>\u2010infected individuals, its role in malaria is still poorly understood, making further investigation essential for assessing its therapeutic potential. We investigated the role of itaconate in both severe and mild malaria using <jats:italic>Plasmodium berghei<\/jats:italic> NK65 (<jats:italic>Pb<\/jats:italic>NK65) and <jats:italic>Plasmodium chabaudi<\/jats:italic> AS (<jats:italic>Pc<\/jats:italic>AS) models, respectively. Using <jats:sup>13<\/jats:sup>C\u2010tracer metabolomics, we detected increased itaconate levels in various organs during infection and identified inflammatory monocytes as the source of this production. Nevertheless, ACOD1 knockout mice displayed no significant changes in phenotype after <jats:italic>Pb<\/jats:italic>NK65 infection, and treatment of <jats:italic>Pb<\/jats:italic>NK65\u2010infected mice with 4\u2010octyl itaconate did not affect disease severity either. However, in the <jats:italic>Pc<\/jats:italic>AS model, ACOD1 deficiency worsened the disease, as indicated by increased weight loss, higher clinical scores, and elevated parasitemia. Therefore, in contrast to the findings in recent literature, our study shows that itaconate does not contribute to susceptibility, but rather provides limited protection to malaria.<\/jats:p>","DOI":"10.1002\/eji.202451595","type":"journal-article","created":{"date-parts":[[2025,5,10]],"date-time":"2025-05-10T00:30:45Z","timestamp":1746837045000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Itaconate Has Limited Protective Effects in Experimental Malaria Models"],"prefix":"10.1002","volume":"55","author":[{"given":"Fran","family":"Prenen","sequence":"first","affiliation":[{"name":"Laboratory of Immunoparasitology Department of Microbiology Immunology and Transplantation Rega Institute for Medical Research KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Pollenus","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoparasitology Department of Microbiology Immunology and Transplantation Rega Institute for Medical Research KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanne","family":"Meers","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoparasitology Department of Microbiology Immunology and Transplantation Rega Institute for Medical Research KU Leuven  Leuven Belgium"},{"name":"Laboratory of Immunobiology Department of Microbiology Immunology and Transplantation Rega Institute for Medical Research KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofie","family":"Knoops","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoparasitology Department of Microbiology Immunology and Transplantation Rega Institute for Medical Research KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Sadler","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoparasitology Department of Microbiology Immunology and Transplantation Rega Institute for Medical Research KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot","family":"Deckers","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoparasitology Department of Microbiology Immunology and Transplantation Rega Institute for Medical Research KU Leuven  Leuven Belgium"},{"name":"Laboratory of Host\u2010Pathogen Interactions Department of Pathology University of Utah  Salt Lake City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evanna L.","family":"Mills","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and Virology Dana\u2010Farber Cancer Institute  Boston Massachusetts USA"},{"name":"Department of Immunology Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe E.","family":"Van den Steen","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoparasitology Department of Microbiology Immunology and Transplantation Rega Institute for Medical Research KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.70"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fuv046"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-024-02006-2"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2020.07.002"},{"key":"e_1_2_12_6_1","unstructured":"World Health Organization World Malaria Report 2023 2022"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-200006000-00025"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.23-0022"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1155165"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.04.016"},{"key":"e_1_2_12_11_1","article-title":"Reprogramming of Host Energy Metabolism Mediated by the TNF\u2010iNOS\u2010HIF\u20101\u03b1 Axis Plays a Key Role in Host Resistance to Plasmodium Infection","author":"Matteucci K. 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