Liver stage malaria infection is controlled by host regulators of lipid peroxidation

Cell Death Differ. 2020 Jan;27(1):44-54. doi: 10.1038/s41418-019-0338-1. Epub 2019 May 7.


The facets of host control during Plasmodium liver infection remain largely unknown. We find that the SLC7a11-GPX4 pathway, which has been associated with the production of reactive oxygen species, lipid peroxidation, and a form of cell death called ferroptosis, plays a critical role in control of Plasmodium liver stage infection. Specifically, blocking GPX4 or SLC7a11 dramatically reduces Plasmodium liver stage parasite infection. In contrast, blocking negative regulators of this pathway, NOX1 and TFR1, leads to an increase in liver stage infection. We have shown previously that increased levels of P53 reduces Plasmodium LS burden in an apoptosis-independent manner. Here, we demonstrate that increased P53 is unable to control parasite burden during NOX1 or TFR1 knockdown, or in the presence of ROS scavenging or when lipid peroxidation is blocked. Additionally, SLC7a11 inhibitors Erastin and Sorafenib reduce infection. Thus, blocking the host SLC7a11-GPX4 pathway serves to selectively elevate lipid peroxides in infected cells, which localize within the parasite and lead to the elimination of liver stage parasites.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Transport System y+ / antagonists & inhibitors
  • Amino Acid Transport System y+ / metabolism*
  • Animals
  • Cell Line
  • Cells, Cultured
  • Ferroptosis
  • Lipid Peroxidation*
  • Liver Diseases / metabolism*
  • Liver Diseases / parasitology*
  • Malaria / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NADPH Oxidase 1 / genetics
  • Phospholipid Hydroperoxide Glutathione Peroxidase / antagonists & inhibitors
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptors, Transferrin / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53 / metabolism


  • Amino Acid Transport System y+
  • Reactive Oxygen Species
  • Receptors, Transferrin
  • Slc7a11 protein, mouse
  • Tfrc protein, mouse
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • glutathione peroxidase 4, mouse
  • NADPH Oxidase 1
  • NOX1 protein, mouse