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Although macrophages and neutrophils are key players in this process, the mechanisms governing their crosstalk in SIMI remain unclear. Here, we demonstrate that the complement C3a receptor 1 (C3aR1) critically mediates this interaction. Using a cecal ligation and puncture (CLP)\u2010induced SIMI rat model and an in\u00a0vitro co\u2010culture system with THP\u20101\u2010derived macrophages, HL\u201060 cells and AC16 cardiomyocytes, we show that C3aR1 promotes macrophage M1 polarisation via the TLR4\/NF\u2010\u03baB pathway. The activated M1 macrophages subsequently trigger neutrophil necroptosis, leading to the release of chemokines and establishing a self\u2010amplifying inflammatory loop from M1 polarisation to neutrophil necroptosis and cardiomyocyte injury, ultimately resulting in cardiac dysfunction. Cardiac\u2010specific knockdown of C3aR1 in\u00a0vivo attenuated myocardial damage, reduced inflammatory cell infiltration and improved cardiac function. Our findings identify C3aR1 as a key molecular hub orchestrating macrophage\u2010neutrophil crosstalk in SIMI and highlight its potential as a therapeutic target for mitigating sepsis\u2010induced cardiac complications.<\/jats:p>","DOI":"10.1111\/jcmm.71145","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T03:35:28Z","timestamp":1776656128000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Macrophage\n                    <scp>C3aR1<\/scp>\n                    Mediates Sepsis\u2010Induced Myocardial Injury by Triggering Neutrophil Necroptosis"],"prefix":"10.1111","volume":"30","author":[{"given":"Jianbo","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory of Microecology\u2010Immune Regulatory Network and Related Diseases, Basic Medical College Jiamusi University  Jiamusi Heilongjiang China"},{"name":"Department of Critical Care Medicine Hanchuan People's Hospital  Xiaogan Hubei Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhilei","family":"He","sequence":"additional","affiliation":[{"name":"Teaching and Research Section of Physiology, the Basic Medical College Jiamusi University  Jiamusi Heilongjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rubing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine Hanchuan People's Hospital  Xiaogan Hubei Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaonan","family":"Peng","sequence":"additional","affiliation":[{"name":"Teaching and Research Section of Physiology, the Basic Medical College Jiamusi University  Jiamusi Heilongjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziteng","family":"Cai","sequence":"additional","affiliation":[{"name":"Teaching and Research Section of Physiology, the Basic Medical College Jiamusi University  Jiamusi Heilongjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Zhao","sequence":"additional","affiliation":[{"name":"Teaching and Research Section of Physiology, the Basic Medical College Jiamusi University  Jiamusi Heilongjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1425-0214","authenticated-orcid":false,"given":"Weiqun","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Microecology\u2010Immune Regulatory Network and Related Diseases, Basic Medical College Jiamusi University  Jiamusi Heilongjiang China"},{"name":"Teaching and Research Section of Physiology, the Basic Medical College Jiamusi University  Jiamusi Heilongjiang China"},{"name":"State Key Laboratory of Neurology and Oncology Drug Development  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,19]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.170149"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01766-7"},{"issue":"4","key":"e_1_2_12_4_1","first-page":"300","article-title":"Myocardial Dysfunction and Its Prognostic Utility in Sepsis and Septic Shock","volume":"59","author":"Delgado\u2010Serrano J. 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