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However, how cardiac repair can be achieved by timely resolution of inflammation and cardiac fibrosis remains incompletely understood. Our previous findings have shown that dual-specificity phosphatase 6 (DUSP6) is a regeneration repressor from zebrafish to rats. In this study, we found that intravenous administration of the DUSP6 inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI) improved heart function and reduced cardiac fibrosis in MI rats. Mechanistic analysis revealed that BCI attenuated macrophage inflammation through NF-\u03baB and p38 signaling, independent of DUSP6 inhibition, leading to the downregulation of various cytokines and chemokines. In addition, BCI suppressed differentiation-related signaling pathways and decreased bone-marrow cell differentiation into macrophages through inhibiting DUSP6. Furthermore, intramyocardial injection of poly (D, L-lactic-co-glycolic acid)-loaded BCI after MI had a notable effect on cardiac repair. In summary, BCI improves heart function and reduces abnormal cardiac remodeling by inhibiting macrophage formation and inflammation post-MI, thus providing a promising pro-drug candidate for the treatment of MI and related heart diseases.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/dmm.049662","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T12:49:55Z","timestamp":1670417395000},"source":"Crossref","is-referenced-by-count":17,"title":["A DUSP6 inhibitor suppresses inflammatory cardiac remodeling and improves heart function after myocardial infarction"],"prefix":"10.1242","volume":"16","author":[{"given":"Zongwang","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Molecular Medicine, College of Future Technology, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University 1 Beijing Key Laboratory of Cardiometabolic Molecular Medicine , , Beijing 100871 , China"},{"name":"Peking University-Nanjing Institute of Translational Medicine 2 , Nanjing 211800 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Chen","sequence":"additional","affiliation":[{"name":"Peking University-Nanjing Institute of Translational Medicine 2 , Nanjing 211800 , China"},{"name":"Academy for Advanced Interdisciplinary Studies, Peking University 3 Laboratory of Biomaterials and Regenerative Medicine , , Beijing 100871 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixia","family":"Zheng","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Future Technology, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University 1 Beijing Key Laboratory of Cardiometabolic Molecular Medicine , , Beijing 100871 , China"},{"name":"Peking University-Nanjing Institute of Translational Medicine 2 , Nanjing 211800 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyong","family":"Du","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Future Technology, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University 1 Beijing Key Laboratory of Cardiometabolic Molecular Medicine , , Beijing 100871 , China"},{"name":"Peking University-Nanjing Institute of Translational Medicine 2 , Nanjing 211800 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shicheng","family":"Wei","sequence":"additional","affiliation":[{"name":"Academy for Advanced Interdisciplinary Studies, Peking University 3 Laboratory of Biomaterials and Regenerative Medicine , , Beijing 100871 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6490-2965","authenticated-orcid":false,"given":"Xiaojun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Future Technology, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University 1 Beijing Key Laboratory of Cardiometabolic Molecular Medicine , , Beijing 100871 , China"},{"name":"Peking University-Nanjing Institute of Translational Medicine 2 , Nanjing 211800 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8438-4782","authenticated-orcid":false,"given":"Jing-Wei","family":"Xiong","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, College of Future Technology, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University 1 Beijing Key Laboratory of Cardiometabolic Molecular Medicine , , Beijing 100871 , China"},{"name":"Peking University-Nanjing Institute of Translational Medicine 2 , Nanjing 211800 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2022,12,7]]},"reference":[{"key":"2023060207544477500_DMM049662C1","doi-asserted-by":"publisher","first-page":"14","DOI":"10.20892\/j.issn.2095-3941.2017.0107","article-title":"Dual-specificity phosphatase 6 (DUSP6): a review of its molecular characteristics and clinical relevance in cancer","volume":"15","author":"Ahmad","year":"2018","journal-title":"Cancer Biol. 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