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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.<\/jats:p>","DOI":"10.1038\/s41467-024-54908-5","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T11:40:34Z","timestamp":1736509234000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Small-molecule-induced ERBB4 activation to treat heart failure"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7661-367X","authenticated-orcid":false,"given":"Julie M. 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