2. Academic Validation
  3. Inhibition of DYRK1B BY C81 impedes inflammatory processes in leukocytes by reducing STAT3 activity

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

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. robert.fuerst@cup.lmu.de.
  • 13 Pharmaceutical Biology, Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University Munich, Munich, Germany. robert.fuerst@cup.lmu.de.
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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