Small-molecule-induced ERBB4 activation to treat heart failure

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, Antoine A. F. Vries, Nele Vandersickel, Daniël A. Pijnappels, Dominique Audenaert, H. Llewelyn Roderick, Hans Winter, Gilles W. Keulenaer and Vincent F. M. Segers ()
Additional contact information
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
Eike M. Wülfers: Ghent University
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
H. Llewelyn Roderick: KU Leuven
Hans Winter: University of Antwerp
Gilles W. Keulenaer: University of Antwerp
Vincent F. M. Segers: University of Antwerp

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-54908-5

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