2. Academic Validation
  3. JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation

JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation

  • EMBO Mol Med. 2025 Aug;17(8):2040-2070. doi: 10.1038/s44321-025-00264-w.
Fran Prenen # 1,  Leen Vandermosten # 1,  Sofie Knoops 1,  Emilie Pollenus 1,  Hendrik Possemiers 1,  Pauline Dagneau de Richecour 1,  Giorgio Caratti 2 3,  Christopher Cawthorne 4,  Sabine Vettorazzi 2,  Yevva Cranshoff 1,  Dominique Schols 5,  Sandra Claes 5,  Christophe M Deroose 4,  Uwe Himmelreich 6,  Jan Tuckermann 2,  Philippe E Van den Steen 7
Affiliations

Affiliations

  • 1 Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, 3000, Belgium.
  • 2 Institute of Molecular Endocrinology and Physiology, German Center for Child and Adolescent Health (DZKJ), partner site Ulm, Ulm University, Ulm, 89081, Germany.
  • 3 Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK.
  • 4 Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, 3000, Belgium.
  • 5 Laboratory of Molecular, Structural and Translational Virology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, 3000, Belgium.
  • 6 Biomedical MRI, Department of Imaging and Pathology, 3000 KU Leuven, Leuven, Belgium.
  • 7 Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, 3000, Belgium. philippe.vandensteen@kuleuven.be.
  • # Contributed equally.
PMID: 40702267 DOI: 10.1038/s44321-025-00264-w
Abstract

Disease tolerance is a key defense mechanism that limits damage to the host without directly reducing pathogen levels. In malaria, these mechanisms are essential for preventing severe disease and death but remain poorly understood. In this study, we show that Glucocorticoid Receptor (GR)-mediated processes play a vital role in disease tolerance during Plasmodium chabaudi AS Infection. GR deletion in infected mice resulted in lethal hypoglycemia and a cytokine storm. Hypoglycemia was driven by severe metabolic dysfunction in the liver and spleen, characterized by increased glucose uptake, glycogen depletion, a dominant glycolytic profile and reduced gluconeogenic gene expression. Importantly, this hypoglycemic state was strongly associated with overactivation of the JAK/STAT pathway and excessive cytokine expression. Treatment with the JAK1/2 inhibitor ruxolitinib significantly improved survival by preventing lethal hypoglycemia and suppressing hyperinflammation. Our findings reveal a novel link between GR signaling, STAT3 activation, cytokine expression and glucose metabolism during severe malaria. This underscores the critical role of GR-mediated processes in disease tolerance and highlights ruxolitinib as a promising Adjuvant therapy for managing life-threatening metabolic complications in malaria.

Keywords

Glucocorticoid Receptor; Hypoglycemia; Malaria; Ruxolitinib; Tolerance.

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