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In this study, we identified the nuclear receptor Nr4a1 as a crucial regulator of this regenerative process in zebrafish. Loss of Nr4a1 function led to a prolonged and excessive inflammatory response, disrupted neutrophil migration, delayed fibrin clearance, and ultimately impaired heart regeneration. Transcriptome-wide RNA-seq analysis at different injury stages revealed molecular disruptions associated with dysregulated inflammation and fibrosis in nr4a1 mutants. Notably, partial inhibition of the pro-inflammatory cytokine Tnf\u03b1 rescued heart regeneration in the nr4a1 mutants, highlighting the therapeutic potential of modulating inflammation. Our findings suggest that Nr4a1 plays a crucial role in orchestrating the immune response during heart regeneration and may serve as a valuable target for enhancing cardiac repair following injury.<\/jats:p>","DOI":"10.1242\/dev.204395","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T16:29:31Z","timestamp":1750782571000},"source":"Crossref","is-referenced-by-count":13,"title":["Nr4a1 modulates inflammation and heart regeneration in zebrafish"],"prefix":"10.1242","volume":"152","author":[{"given":"Dong","family":"Feng","sequence":"first","affiliation":[{"name":"University of North Carolina 1 Department of Pathology and Laboratory Medicine , , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"McAllister Heart Institute, University of North Carolina 2 , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhan","family":"Dong","sequence":"additional","affiliation":[{"name":"University of North Carolina 1 Department of Pathology and Laboratory Medicine , , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"McAllister Heart Institute, University of North Carolina 2 , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Song","sequence":"additional","affiliation":[{"name":"University of North Carolina 1 Department of Pathology and Laboratory Medicine , , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"McAllister Heart Institute, University of North Carolina 2 , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Yapundich","sequence":"additional","affiliation":[{"name":"University of North Carolina 1 Department of Pathology and Laboratory Medicine , , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"McAllister Heart Institute, University of North Carolina 2 , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifang","family":"Xie","sequence":"additional","affiliation":[{"name":"University of North Carolina 1 Department of Pathology and Laboratory Medicine , , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"McAllister Heart Institute, University of North Carolina 2 , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Spurlock","sequence":"additional","affiliation":[{"name":"University of North Carolina 1 Department of Pathology and Laboratory Medicine , , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"McAllister Heart Institute, University of North Carolina 2 , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Lyu","sequence":"additional","affiliation":[{"name":"University of North Carolina 1 Department of Pathology and Laboratory Medicine , , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"McAllister Heart Institute, University of North Carolina 2 , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Landry","family":"Kuehn","sequence":"additional","affiliation":[{"name":"University of North Carolina 1 Department of Pathology and Laboratory Medicine , , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"McAllister Heart Institute, University of North Carolina 2 , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Qian","sequence":"additional","affiliation":[{"name":"University of North Carolina 1 Department of Pathology and Laboratory Medicine , , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"McAllister Heart Institute, University of North Carolina 2 , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0035-3570","authenticated-orcid":false,"given":"Jiandong","family":"Liu","sequence":"additional","affiliation":[{"name":"University of North Carolina 1 Department of Pathology and Laboratory Medicine , , Chapel Hill, NC 27599 ,","place":["USA"]},{"name":"McAllister Heart Institute, University of North Carolina 2 , Chapel Hill, NC 27599 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,7,11]]},"reference":[{"key":"2026090107082547700_DEV204395C1","doi-asserted-by":"publisher","first-page":"eabg6497","DOI":"10.1126\/sciadv.abg6497","article-title":"Interleukin-11 signaling promotes cellular reprogramming and limits fibrotic scarring during tissue regeneration","volume":"7","author":"Allanki","year":"2021","journal-title":"Sci. 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