Inhibition of DYRK1B BY C81 impedes inflammatory processes in leukocytes by reducing STAT3 activity

  • Cell Mol Life Sci. 2025 Feb 22;82(1):85. doi: 10.1007/s00018-025-05579-y.
Sarah Ciurus  1 ,  Mohammed A F Elewa  2  3 ,  Megan A Palmer  2 ,  Anne Wolf  4  5 ,  Mandy Hector  4 ,  Dominik C Fuhrmann  2 ,  Dominique Thomas  6  7  8 ,  Robert Gurke  6  7  8 ,  Martin P Schwalm  9 ,  Lena Berger  9 ,  Thomas J Zech  1  10 ,  Luisa D Burgers  1 ,  Rolf Marschalek  1 ,  Gerd Geisslinger  6  7  8 ,  Stefan Knapp  9 ,  Thomas Langmann  4  5 ,  Franz Bracher  11 ,  Andreas Weigert  2 ,  Robert Fürst  12  13
Affiliations
  • 1. Institute of Pharmaceutical Biology, Goethe University Frankfurt, Frankfurt, Germany.
  • 2. Institute of Biochemistry I, Goethe University Frankfurt, Frankfurt, Germany.
  • 3. Department of Biochemistry, Faculty of Pharmacy, Kafr El-Sheikh University, Karf El-Sheikh, Egypt.
  • 4. Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine, University of Cologne, University Hospital Cologne, Cologne, Germany.
  • 5. Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
  • 6. Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt, Germany.
  • 7. Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Frankfurt, Germany.
  • 8. Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), Frankfurt, Germany.
  • 9. Institute of Pharmaceutical Chemistry and Buchmann Institute Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.
  • 10. Pharmaceutical Biology, Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University Munich, Munich, Germany.
  • 11. Pharmaceutical Chemistry, Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University Munich, Munich, Germany.
  • 12. Institute of Pharmaceutical Biology, Goethe University Frankfurt, Frankfurt, Germany. [email protected].
  • 13. Pharmaceutical Biology, Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University Munich, Munich, Germany. [email protected].
PMID: 39985685 DOI: 10.1007/s00018-025-05579-y
Abstract

Chronic inflammatory diseases are a significant global burden and are associated with dysregulated resolution of inflammation. Therefore, promoting the process of resolution is a promising therapeutic approach. This study presents the potent anti-inflammatory and pro-resolving effects of a natural product-derived compound called C81. Administration of C81 in a therapeutic window resolved inflammation in the murine imiquimod-induced psoriasis model, and reduced microglial infiltration in a laser-induced choroidal neovascularisation model. Investigations into the underlying mechanisms of C81 identified the DYRK1B/STAT3 axis as a new regulator of inflammatory processes in leukocytes. The inhibition of DYRK1B by C81 resulted in attenuated STAT3 phosphorylation. The depletion of STAT3-regulated gene expression led to the inhibition of leukocyte adhesion and migration due to reduced Integrin activation, and in addition to the inhibition of the release of pro-inflammatory mediators such as cytokines and eicosanoids. Importantly, the pro-resolving effects of C81 included the cell type-specific induction of Apoptosis in neutrophils and a subsequent increase in efferocytosis. In conclusion, we report the DYRK1B/STAT3 axis as a novel and promising therapeutic target for activating the resolution of inflammation.

Keywords
DYRK1B-STAT3 signaling; Kinase inhibitor; Leukocytes; Natural product; Resolution of inflammation.
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