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Small-molecule-induced ERBB4 activation to treat heart failure

Author

Listed:
  • Julie M. T. Cools

    (University of Antwerp)

  • Bo K. Goovaerts

    (University of Antwerp)

  • Eline Feyen

    (University of Antwerp)

  • Siel Bogaert

    (University of Antwerp)

  • Yile Fu

    (KU Leuven)

  • Céline Civati

    (University of Antwerp)

  • Jens fraeyenhove

    (University of Antwerp)

  • Michiel R. L. Tubeeckx

    (University of Antwerp)

  • Jasper Ott

    (University of Antwerp)

  • Long Nguyen

    (VIB
    Ghent University)

  • Eike M. Wülfers

    (Ghent University
    University of Freiburg)

  • Benji Berlo

    (University of Antwerp)

  • Antoine A. F. Vries

    (Leiden University Medical Center)

  • Nele Vandersickel

    (Ghent University)

  • Daniël A. Pijnappels

    (Leiden University Medical Center)

  • Dominique Audenaert

    (VIB
    Ghent University)

  • H. Llewelyn Roderick

    (KU Leuven)

  • Hans Winter

    (University of Antwerp)

  • Gilles W. Keulenaer

    (University of Antwerp
    ZNA Hospital)

  • Vincent F. M. Segers

    (University of Antwerp
    University Hospital Antwerp)

Abstract

Heart failure is a common and deadly disease requiring new treatments. The neuregulin-1/ERBB4 pathway offers cardioprotective benefits, but using recombinant neuregulin-1 as therapy has limitations due to the need for intravenous delivery and lack of receptor specificity. We hypothesize that small-molecule activation of ERBB4 could protect against heart damage and fibrosis. To test this, we conduct a screening of 10,240 compounds and identify eight structurally similar ones (EF-1 to EF-8) that induce ERBB4 dimerization, with EF-1 being the most effective. EF-1 reduces cell death and hypertrophy in cardiomyocytes and decreases collagen production in cardiac fibroblasts in an ERBB4-dependent manner. In wild-type mice, EF-1 inhibits angiotensin-II-induced fibrosis in males and females and reduces heart damage caused by doxorubicin and myocardial infarction in females, but not in Erbb4-null mice. This study shows that small-molecule ERBB4 activation is feasible and may lead to a novel class of drugs for treating heart failure.

Suggested Citation

  • Julie M. T. Cools & Bo K. Goovaerts & Eline Feyen & Siel Bogaert & Yile Fu & Céline Civati & Jens fraeyenhove & Michiel R. L. Tubeeckx & Jasper Ott & Long Nguyen & Eike M. Wülfers & Benji Berlo & Anto, 2025. "Small-molecule-induced ERBB4 activation to treat heart failure," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-54908-5
    DOI: 10.1038/s41467-024-54908-5
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