{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T20:42:04Z","timestamp":1792269724591,"version":"4.4.0"},"reference-count":44,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Myocardial fibrosis (MF) is a critical pathological substrate of heart failure (HF), and \u03b23\u2010adrenergic receptor (\u03b23\u2010AR) has been implicated in cardiac remodelling with controversial roles. This study aimed to clarify the pro\u2010fibrotic mechanism of \u03b23\u2010AR in cardiac fibroblasts and its association with \u03b2\u2010arrestin2\u2010mediated biased activation. Primary cardiac fibroblasts were isolated from neonatal C57BL\/6 mice and subjected to \u03b23\u2010AR overexpression, agonist (BRL37344) stimulation, antagonist (SR59230A) inhibition, JNK inhibitor (SP600125) treatment, or \u03b2\u2010arrestin2 knockdown via siRNA. RNA sequencing, immunofluorescence, Western blotting, and coimmunoprecipitation assays were performed to explore molecular mechanisms. RNA sequencing identified 577 upregulated and 231 downregulated genes in \u03b23\u2010AR\u2010activated fibroblasts, enriched in extracellular matrix organisation and inflammatory pathways. Functional experiments confirmed that BRL37344 significantly upregulated fibrosis markers (\u03b1\u2010SMA, FN, collagen I\/III) and TGF\u2010\u03b21 expression, which was reversed by SP600125. Notably, inhibition of Gi signalling by pertussis toxin (PTX) failed to block \u03b23\u2010AR\u2010induced fibrosis, while \u03b2\u2010arrestin2 knockdown abrogated JNK\/c\u2010Jun\/TGF\u2010\u03b21 pathway activation. Immunofluorescence and coimmunoprecipitation verified colocalisation and direct interaction between \u03b23\u2010AR and \u03b2\u2010arrestin2, which was enhanced by BRL37344. Our findings demonstrate that \u03b23\u2010AR promotes cardiac fibrosis through \u03b2\u2010arrestin2\u2010mediated biased activation of the JNK\/c\u2010Jun\/TGF\u2010\u03b21 pathway, independent of classical Gi signalling. This study reveals a novel cell\u2010specific signalling mechanism of \u03b23\u2010AR and provides a potential therapeutic target for developing precision drugs against MF and HF.<\/jats:p>","DOI":"10.1111\/jcmm.71305","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:03:28Z","timestamp":1785816208000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["\u03b23\u2010\n                    <scp>AR<\/scp>\n                    \/\u03b2\u2010arrestin2 Interaction Triggers Cardiac Fibrosis Through\n                    <scp>JNK<\/scp>\n                    \/c\u2010Jun Pathway in Cardiac Fibroblasts"],"prefix":"10.1111","volume":"30","author":[{"given":"Zhongcheng","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Cardiology The Jinhua Affiliated Hospital of Wenzhou Medical University  Jinhua Zhejiang China"},{"name":"Department of Cardiology, Shanghai Tong Ren 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