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Thymosin beta-4 (TB4), a short, secreted peptide, was shown to possess a beneficial impact regarding myocardial cell survival, coronary re-growth and progenitor cell activation following myocardial infarction in adult mammals. It equally reduces scarring, however, the precise mechanisms through which the peptide assists this phenomenon have not been properly elucidated. Accordingly, the primary aim of our study was to identify novel molecular contributors responsible for the positive impact of TB4 during the remodeling processes of the infarcted heart. We performed miRNA profiling on adult mice hearts following permanent coronary ligation with or without systemic TB4 injection and searched for targets and novel mechanisms through which TB4 may mitigate pathological scarring in the heart. Our results revealed a significant increase in miR139-5p expression and identified ROCK1 as a potential target protein aligned. Real-time PCR, Western blot and immunostaining on adult mouse hearts and human cardiac cells revealed the peptide indirectly or directly modulates ROCK1 protein levels both in vivo and in vitro. We equally discovered TB4 may reverse or inhibit fibroblast\/myofibroblast transformation and the potential downstream mechanisms by which TB4 alters cellular responses through ROCK1 are cell type specific. Given the beneficial effects of ROCK1 inhibition in various cardiac pathologies, we propose a potential utilization for TB4 as a ROCK1 inhibitor in the future.<\/jats:p>","DOI":"10.3390\/ijms26094131","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T11:48:33Z","timestamp":1745840913000},"page":"4131","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Thymosin Beta-4 Modulates Cardiac Remodeling by Regulating ROCK1 Expression in Adult Mammals"],"prefix":"10.3390","volume":"26","author":[{"given":"Klaudia","family":"Maar","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6340-2942","authenticated-orcid":false,"given":"Jeffrey E.","family":"Thatcher","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Egor","family":"Karpov","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Szilard","family":"Rendeki","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Therapy, University of Pecs Medical School, 7624 Pecs, Hungary"},{"name":"Medical Skills Education and Innovation Centre, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1906-4333","authenticated-orcid":false,"suffix":"Jr.","given":"Ferenc","family":"Gallyas","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1284-9696","authenticated-orcid":false,"given":"Ildiko","family":"Bock-Marquette","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"},{"name":"Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,26]]},"reference":[{"key":"ref_1","unstructured":"WHO (2020). 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