{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:09:20Z","timestamp":1785431360239,"version":"3.56.0"},"reference-count":60,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Horizon 2020 ERA.Net RUS Plus","award":["Nr. IZRPZ0_177566"],"award-info":[{"award-number":["Nr. 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Neuregulin-1\u03b2 (NRG1) has been studied as a cardioprotective factor, yet its mechanisms during DOX treatment, particularly in the presence of cancer, are not well understood. This study evaluated daily recombinant NRG1 co-administered with DOX in 4T1-tumor-bearing female BALB\/c mice. The mice were randomized to saline, DOX (3 mg\/kg i.p. on days 0, 3, 6, 9; cumulatively 12 mg\/kg) or DOX + NRG1 (20 \u00b5g\/kg i.p. daily, starting one day before DOX). Body weight and tumor growth were monitored throughout treatment. Cardiac structure and function were assessed by transthoracic echocardiography at baseline and before sacrifice. Mechanistic studies included left ventricular proteomics and single-cell RNA-seq. We also used human 3D cardiac microtissues and 2D primary cardiac fibroblast-enriched cultures under defined experimental conditions, with targeted fibroblast gene perturbations. We found that early DOX exposure induced systolic dysfunction and pathological remodeling, while daily NRG1 preserved the ejection fraction and attenuated structural changes without impairing anti-tumor efficacy. Proteomic analysis identified Serping1 as one of the most strongly upregulated proteins soon after DOX exposure, an effect that was reversed by NRG1. Notably, Serping1 has not previously been implicated in anthracycline cardiotoxicity or NRG1-mediated protection. Single-cell RNA sequencing localized Serping1 expression to cardiac fibroblasts. Mechanistically, we found that Serping1 modulation was associated with altered Igfbp5 processing and fibroblast survival under DOX-induced stress; its suppression by NRG1 was linked to reduced fibroblast apoptosis and a shift toward a pro-survival-associated state. In human cardiac microtissues, NRG1 treatment or fibroblast-specific Serping1 knockdown accelerated cardiomyocyte contraction dynamics. These changes occurred without an increase in apoptosis and point to a paracrine effect of fibroblasts on cardiomyocyte function. Additionally, scRNA-seq revealed an Erbb4+ fibroblast subpopulation associated with early pro-fibrotic activation that expanded after DOX but was reduced by NRG1. Taken together, NRG1 preserved cardiac function during anthracycline treatment while maintaining anti-tumor efficacy. Our data identify fibroblast-associated signaling, particularly through Serping1, as a potential contributor to the early protective effects of NRG1. These findings add a new dimension to the understanding of NRG1 cardioprotection and suggest that fibroblast\u2013myocyte interactions may contribute to the early cardiac response to DOX.<\/jats:p>","DOI":"10.3390\/ijms27104616","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T12:06:07Z","timestamp":1779365167000},"page":"4616","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuregulin-1\u03b2 Mitigates Doxorubicin-Induced Cardiotoxicity via Serping1 in Cardiac Fibroblasts"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1519-5790","authenticated-orcid":false,"given":"Parisa","family":"Aghagolzadeh","sequence":"first","affiliation":[{"name":"Cardiobiology, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9355-981X","authenticated-orcid":false,"given":"Lifen","family":"Xu","sequence":"additional","affiliation":[{"name":"Cardiobiology, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7299-8861","authenticated-orcid":false,"given":"Philipp","family":"Klinger","sequence":"additional","affiliation":[{"name":"Cardiobiology, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Morandi","sequence":"additional","affiliation":[{"name":"Cardiobiology, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8386-6718","authenticated-orcid":false,"given":"Lilia Maryse","family":"L\u00e9pine","sequence":"additional","affiliation":[{"name":"Cardiobiology, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0200-7938","authenticated-orcid":false,"given":"Lukas","family":"Minder","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8640-6620","authenticated-orcid":false,"given":"Pieter-Jan","family":"Guns","sequence":"additional","affiliation":[{"name":"Laboratory of Physiopharmacology, Faculty of Medicine and Health Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Bosman","sequence":"additional","affiliation":[{"name":"Laboratory of Physiopharmacology, Faculty of Medicine and Health Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-May","family":"Coissieux","sequence":"additional","affiliation":[{"name":"Laboratory of Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Pedrazzini","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Medicine and Sciences, MRC\/BHF Centre of Research Excellence in Advanced Cardiac Therapies, King\u2019s College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3788-4594","authenticated-orcid":false,"given":"Gabriela","family":"Kania","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1790-0190","authenticated-orcid":false,"given":"Marijke","family":"Brink","sequence":"additional","affiliation":[{"name":"Cardiobiology, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, 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