Small-molecule-induced ERBB4 activation to treat heart failure
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.
Authors
- Yile Fu (ORCID: https://orcid.org/0000-0003-0615-1152)
- Eike M. Wülfers (ORCID: https://orcid.org/0000-0002-8292-6514)
- Jens Van fraeyenhove (ORCID: https://orcid.org/0000-0003-4891-4402)
- Céline Civati
- Juliane Ott
- Antoine A.F. de Vries (ORCID: https://orcid.org/0000-0002-4787-7155)
- Vincent F. M. Segers (ORCID: https://orcid.org/0000-0001-7796-2222)
- Long Nguyen (ORCID: https://orcid.org/0000-0003-2654-7816)
- H. Llewelyn Roderick (ORCID: https://orcid.org/0000-0001-7065-3523)
- Dominique Audenaert (ORCID: https://orcid.org/0000-0002-1962-1136)
- Daniël A. Pijnappels (ORCID: https://orcid.org/0000-0001-6731-4125)
- Michiel Tubeeckx (ORCID: https://orcid.org/0000-0002-1337-0727)
- Hans De Winter
- Nele Vandersickel (ORCID: https://orcid.org/0000-0002-8827-5302)
- Julie Cools (ORCID: https://orcid.org/0000-0001-7661-367X)
- Eline Feyen (ORCID: https://orcid.org/0000-0002-2275-0983)
- Bo Goovaerts
- Siel Van den Bogaert
- B Van Berlo
- Gilles W. De Keulenaer
Institutions
- University of Antwerp (BE)
- University of Freiburg (DE)
- Leiden University Medical Center (NL)
- Ghent University (BE)
- Antwerp University Hospital (BE)
- Universitäts-Herzzentrum Freiburg-Bad Krozingen (DE)
- Ziekenhuisnetwerk Antwerpen Stuivenberg (BE)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-10
- DOI
- https://doi.org/10.1038/s41467-024-54908-5
- Citations
- 12
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 12.54
Funders
- Universiteit Leiden
- Leids Universitair Medisch Centrum
- Vlaamse Interuniversitaire Raad
- Universiteit Antwerpen
- Vlaamse regering