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Although astrocytes constitute essential components of the BBB neurovascular unit, their immunoregulatory functions during CM pathogenesis remain elusive. Clinical evidence of altered copper homeostasis in patients with CM, coupled with known associations between copper dysregulation and astrocyte reactivity, prompted investigation of cuproptosis\u2014a copper-dependent programmed cell death pathway\u2014in the disease progression of CM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using a\n                      <jats:italic>P. berghei<\/jats:italic>\n                      ANKA (\n                      <jats:italic>Pb<\/jats:italic>\n                      A)-induced experimental CM (ECM) model in C57BL\/6 mice, we evaluated pharmacological modulation with copper ionophore disulfiram (DSF) versus copper chelator tetrathiomolybdate (TTM). Parallel in vitro experiments assessed astrocytes stimulated by\n                      <jats:italic>Pb<\/jats:italic>\n                      A-infected red blood cells (iRBCs)\/blood-stage soluble antigen (\n                      <jats:italic>Pb<\/jats:italic>\n                      Ag) under DSF-CuCl\n                      <jats:sub>2<\/jats:sub>\n                      or TTM-CuCl\n                      <jats:sub>2<\/jats:sub>\n                      treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ECM mice demonstrated significant cerebral copper accumulation with concomitant upregulation of cuproptosis markers (SLC31A1, FDX1, DLAT, and DLST) and downregulation of ATP7A copper transporter. DSF administration exacerbated ECM progression through amplified parasitemia, aggravated BBB permeability, cerebral edema, and neuroinflammatory responses, whereas TTM treatment counteracted these pathological manifestations. Immunohistochemical analysis revealed DSF-induced astrocyte reactivity (GFAP\n                      <jats:sup>+<\/jats:sup>\n                      \/Serping1\n                      <jats:sup>+<\/jats:sup>\n                      ) with colocalization of cuproptosis markers (GFAP\n                      <jats:sup>+<\/jats:sup>\n                      -SLC31A1\n                      <jats:sup>+<\/jats:sup>\n                      \/FDX1\n                      <jats:sup>+<\/jats:sup>\n                      \/DLAT\n                      <jats:sup>+<\/jats:sup>\n                      \/DLST\n                      <jats:sup>+<\/jats:sup>\n                      ), contrasting with TTM-mediated suppression. In vitro, DSF-CuCl\n                      <jats:sub>2<\/jats:sub>\n                      treatment augmented iRBC-stimulated astrocyte expression of reactivity markers (GFAP and Serping1), cuproptosis regulators (SLC31A1, FDX1, DLAT, and DLST), and proinflammatory mediators (CXCL10, tumor necrosis factor (TNF)-\u0251, interleukin (IL)-1\u03b2, and IL-6), but conversely reduced\n                      <jats:italic>Pb<\/jats:italic>\n                      Ag-stimulated cell viability. These effects were reversed by TTM-CuCl\n                      <jats:sub>2<\/jats:sub>\n                      treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings establish that cuproptosis exacerbates ECM pathogenesis by promoting astrocyte reactivity, highlighting copper homeostasis modulation as a potential therapeutic strategy for CM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s13071-025-07107-0","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T13:18:17Z","timestamp":1762780697000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cuproptosis-driven astrocyte reactivity exacerbates experimental cerebral malaria pathogenesis"],"prefix":"10.1186","volume":"18","author":[{"given":"Xinpeng","family":"Hou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumei","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoran","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chufang","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamei","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lirong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajing","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingda","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zujun","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minqiu","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenlong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobao","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"7107_CR1","volume-title":"World malaria report 2024","author":"WHO","year":"2024","unstructured":"WHO. 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