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Their polarization is essential for maintaining cardiac function. This study aims to explore the role of MCPIP1(Monocyte chemotactic protein\u2010induced protein 1) in regulating macrophage polarization and its impact on heart\u2010spleen interactions during MI recovery. The role of MCPIP1 was investigated using histological staining, RNA sequencing of bone marrow\u2010derived macrophages, co\u2010culture experiments, and validated by western blot. Compared to controls, myeloid MCPIP1\u2010deficient mice had lower survival rates, larger infarction areas, and more severe inflammatory responses after MI. This was due to increased M1 polarization and impaired conversion to the M2 phenotype. Ferroptosis activation in MCPIP1\u2010deficient macrophages was inhibited by Fer\u20101 and PFT\u2010\u03b1, which promoted M2 polarization and fibroblast activation into myofibroblasts. MCPIP1\u2010deficient MI mice also showed splenomegaly and elevated levels of circulating macrophages, indicating excessive extramedullary hematopoiesis. Splenectomy improved survival rates and reduced infarction size in MCPIP1\u2010deficient mice. MCPIP1 suppresses the P53\/ferroptosis pathway to regulate macrophage polarization and TGF\u2010\u03b2\/SMAD3\u2010mediated fibroblast activation. Its deficiency exacerbates inflammation through abnormal splenic macrophage output, impairing cardiac repair. MCPIP1 is a promising therapeutic target for modulating ferroptosis and heart\u2010spleen communication to protect cardiac function following MI.<\/jats:p>","DOI":"10.1002\/advs.202500747","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T06:33:43Z","timestamp":1745649223000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The Role of MCPIP1 in Macrophage Polarization and Cardiac Function Post\u2010Myocardial Infarction"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0338-9288","authenticated-orcid":false,"given":"Xingxu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiology Shanghai Tenth People's Hospital Tongji University School of Medicine 301 Middle Yanchang Road Shanghai 200072 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Tenth People's Hospital Tongji University School of Medicine 301 Middle Yanchang Road Shanghai 200072 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Tenth People's Hospital Tongji University School of Medicine 301 Middle Yanchang Road Shanghai 200072 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Tenth People's Hospital Tongji University School of Medicine 301 Middle Yanchang Road Shanghai 200072 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Health Policy and Management Fielding School of Public Health University of California 650 Charles E Young Dr S Los Angeles CA 90095 United\u00a0States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhong","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific Western University of Health Sciences 309 E. 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