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Upon infection of the host RBCs,\n                      <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                      produces hemozoin, a crystal form of heme generated following the degradation of hemoglobin by the parasite. Here, we show that the endothelial barrier-disrupting activity is found entirely in the hemozoin fraction of\n                      <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                      -iRBCs. This activity is not caused by the hemozoin crystal itself, which is not able to induce barrier disruption, but by the biomolecules that are associated with it. Treatment of purified\n                      <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                      hemozoin with proteases inhibits the disruption of endothelial barrier integrity caused by the hemozoin, indicating an important role for proteins in the disruption of the barrier. Conversely, treatment with nucleases did not affect hemozoin barrier-disrupting activity. These results identify a key molecular mechanism in the\n                      <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                      -mediated brain endothelial barrier disruption during cerebral malaria and may open new avenues for the treatment of this complication.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        While several specific biomolecules have been proposed to contribute to the disruption of endothelial barrier integrity in cerebral malaria, no single\n                        <jats:italic toggle=\"yes\">Plasmodium falciparum-<\/jats:italic>\n                        or host-derived factor has been definitively identified as the primary driver of this disruption. Here, we identify the brain endothelial barrier-disruptive\n                        <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                        -infected red blood cell (iRBC)-derived activity to be caused by biomolecules bound to hemozoin, identifying a key, novel mechanism in the pathogenesis of cerebral malaria. The finding that\n                        <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                        hemozoin also disrupts a pulmonary endothelial cell barrier opens the possibility that this mechanism underlies other severe malaria complications. The implication of\n                        <jats:italic toggle=\"yes\">P. falciparum-<\/jats:italic>\n                        iRBC-derived proteins in this mechanism is in line with previous reports, providing a novel interpretation of these findings in the context of hemozoin-binding. This knowledge provides a new perspective in the search for specific molecules and mechanisms involved in barrier disruption, which may lead to the development of much-needed specific treatments for cerebral malaria.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00313-26","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T09:55:57Z","timestamp":1776678957000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["<i>Plasmodium falciparum<\/i>\n                    hemozoin-associated biomolecules induce brain endothelial cell barrier disruption in an\n                    <i>in vitro<\/i>\n                    model of cerebral malaria"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8462-5275","authenticated-orcid":true,"given":"Kelly A.","family":"Crotty","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0190ak572","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, NYU School of Medicine","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana","family":"Clotea","sequence":"additional","affiliation":[{"name":"Proteomics Laboratory, NYU School of Medicine","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrix","family":"Ueberheide","sequence":"additional","affiliation":[{"name":"Proteomics Laboratory, NYU School of Medicine","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Cammer","sequence":"additional","affiliation":[{"name":"Microscopy Laboratory, NYU School of Medicine","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Sall","sequence":"additional","affiliation":[{"name":"Microscopy Laboratory, NYU School of Medicine","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Liang","sequence":"additional","affiliation":[{"name":"Microscopy Laboratory, NYU School of Medicine","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0060-3405","authenticated-orcid":false,"given":"Ana","family":"Rodriguez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0190ak572","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, NYU School of Medicine","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","unstructured":"WHO. 2024 The top 10 causes of death. 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