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Macrophage\u2010mediated efferocytosis of infiltrating neutrophils is crucial for resolving inflammation and restoring homeostasis post\u2010MI. However, the specific regulatory mechanisms governing neutrophil clearance and efferocytosis remain undefined. This study demonstrates a significant correlation between increased IRGM expression in peripheral blood neutrophils of patients with MI and improved prognostic outcomes. Neutrophil\u2010specific deletion of Irgm1 exacerbates cardiac dysfunction, impairs post\u2010MI repair, and hinders neutrophil clearance and efferocytosis. Irgm1 deficiency further delays neutrophil clearance in the heart and extends neutrophil survival. Mechanistically, Irgm1 directly interacts with PDIA3, promoting its autophagic degradation, which in turn activates the endoplasmic reticulum stress\/NF\u2010\u03baB\/caspase\u20103 pathway to facilitate neutrophil clearance and efferocytosis. In vivo administration of LOC14 significantly reduces tissue damage and enhances cardiac recovery in neutrophil Irgm1\u2010deficient mice post\u2010MI. These findings highlight the pivotal role of the Irgm1\u2010PDIA3 axis in facilitating cardiac repair post\u2010MI by promoting neutrophil clearance. LOC14 may serve as a potential therapeutic agent to enhance cardiac function post\u2010MI, particularly in Irgm1\u2010deficient cases.<\/jats:p>","DOI":"10.1002\/advs.202514863","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T19:30:40Z","timestamp":1772998240000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Irgm1 Improves Postinfarction Cardiac Repair by Promoting Neutrophil Clearance and Efferocytosis"],"prefix":"10.1002","volume":"13","author":[{"given":"Zeng","family":"Wang","sequence":"first","affiliation":[{"name":"The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lai","family":"Wei","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Myocardial Ischemia, Chinese 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