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<p>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.</p>

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Small-molecule-induced ERBB4 activation to treat heart failure

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月10日

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  • Julie M. T. Cools,
  • Bo K. Goovaerts,
  • Eline Feyen,
  • Siel Van den Bogaert,
  • Yile Fu,
  • Céline Civati,
  • Jens Van fraeyenhove,
  • Michiel R. L. Tubeeckx,
  • Jasper Ott,
  • Long Nguyen,
  • Eike M. Wülfers,
  • Benji Van Berlo,
  • Antoine A. F. De Vries,
  • Nele Vandersickel,
  • Daniël A. Pijnappels,
  • Dominique Audenaert,
  • H. Llewelyn Roderick,
  • Hans De Winter,
  • Gilles W. De Keulenaer,
  • Vincent F. M. Segers

摘要

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.