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Background <p>Cerebral malaria (CM), a lethal neurological complication of <i>Plasmodium falciparum</i>, is characterized by blood–brain barrier (BBB) disruption. 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—a copper-dependent programmed cell death pathway—in the disease progression of CM.</p> Methods <p>Using a <i>P. berghei</i> ANKA (<i>Pb</i>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 <i>Pb</i>A-infected red blood cells (iRBCs)/blood-stage soluble antigen (<i>Pb</i>Ag) under DSF-CuCl<sub>2</sub> or TTM-CuCl<sub>2</sub> treatment.</p> Results <p>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<sup>+</sup>/Serping1<sup>+</sup>) with colocalization of cuproptosis markers (GFAP<sup>+</sup>-SLC31A1<sup>+</sup>/FDX1<sup>+</sup>/DLAT<sup>+</sup>/DLST<sup>+</sup>), contrasting with TTM-mediated suppression. In vitro, DSF-CuCl<sub>2</sub> 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)-ɑ, interleukin (IL)-1β, and IL-6), but conversely reduced <i>Pb</i>Ag-stimulated cell viability. These effects were reversed by TTM-CuCl<sub>2</sub> treatment.</p> Conclusions <p>These findings establish that cuproptosis exacerbates ECM pathogenesis by promoting astrocyte reactivity, highlighting copper homeostasis modulation as a potential therapeutic strategy for CM.</p> Graphical Abstract <p></p>

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Cuproptosis-driven astrocyte reactivity exacerbates experimental cerebral malaria pathogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月10日

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  • Xinpeng Hou,
  • Xiumei Mo,
  • Xiaoran Zhang,
  • Qi Wang,
  • Xiaoyan Chen,
  • Chufang Lai,
  • Jiamei Gao,
  • Lirong Wu,
  • Wenbin Liu,
  • Jiajing He,
  • Xingda Zeng,
  • Hui Yin,
  • Zujun Deng,
  • Tao Liu,
  • Minqiu Ye,
  • Zhenlong Liu,
  • Xiaobao Jin,
  • Jianping Song,
  • Jie Wang,
  • Bo Huang

摘要

Background

Cerebral malaria (CM), a lethal neurological complication of Plasmodium falciparum, is characterized by blood–brain barrier (BBB) disruption. 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—a copper-dependent programmed cell death pathway—in the disease progression of CM.

Methods

Using a P. berghei ANKA (PbA)-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 PbA-infected red blood cells (iRBCs)/blood-stage soluble antigen (PbAg) under DSF-CuCl2 or TTM-CuCl2 treatment.

Results

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+/Serping1+) with colocalization of cuproptosis markers (GFAP+-SLC31A1+/FDX1+/DLAT+/DLST+), contrasting with TTM-mediated suppression. In vitro, DSF-CuCl2 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)-ɑ, interleukin (IL)-1β, and IL-6), but conversely reduced PbAg-stimulated cell viability. These effects were reversed by TTM-CuCl2 treatment.

Conclusions

These findings establish that cuproptosis exacerbates ECM pathogenesis by promoting astrocyte reactivity, highlighting copper homeostasis modulation as a potential therapeutic strategy for CM.

Graphical Abstract