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This study investigates the role of macrophages in iron overload\u2010related hepatocyte damage during liver I\/R.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Liver biopsies from patients undergoing partial hepatectomy with or without hepatic portal occlusion were recruited and markers of hepatocyte cell death and macrophage extracellular traps (METs) were detected. A murine hepatic I\/R model was also established in high\u2010iron diet\u2010fed mice. Ferrostatin\u20101 and deferoxamine were administered to investigate the role of ferroptosis in hepatic I\/R injury. The macrophage inhibitor liposome\u2010encapsulated clodronate was used to investigate the interaction between macrophages and ferroptosis. AML12 hepatocytes and RAW264.7 macrophages were co\u2010cultured <jats:italic>in vitro<\/jats:italic>. An inhibitor of macrophage extracellular traps was used to evaluate the role and mechanism of these traps and ferroptosis in hepatic I\/R injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Hepatocyte macrophage extracellular trap formation and ferroptosis were greater in patients who underwent hepatectomy with hepatic portal occlusion and in mice subjected to hepatic I\/R. Macrophage extracellular traps increased when macrophages were subjected to hypoxia\/reoxygenation and when they were co\u2010cultured with hepatocytes. Ferroptosis increased and post\u2010hypoxic hepatocyte survival decreased, which were reversed by inhibition of macrophage extracellular traps. Ferroptosis inhibition attenuated post\u2010ischaemic liver damage. Moreover, iron overload induced hepatic ferroptosis and exacerbated post\u2010ischaemic liver damage, which were reversed by the iron chelator.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Macrophage extracellular traps are in volved in regulating ferroptosis highlighting the therapeutic potential of macrophage extracellular traps and ferroptosis inhibition in reducing liver I\/R injury.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15518","type":"journal-article","created":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T16:51:05Z","timestamp":1620492665000},"page":"3783-3796","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["Macrophage extracellular traps aggravate iron overload\u2010related liver ischaemia\/reperfusion injury"],"prefix":"10.1111","volume":"178","author":[{"given":"Shan","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Anesthesiology The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"},{"name":"Department of Anesthesiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine Chinese Academy of Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoliang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingping","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongdong","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haobo","family":"Li","sequence":"additional","affiliation":[{"name":"Corrigan Minehan Heart Center Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqing","family":"Hei","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5284-9159","authenticated-orcid":false,"given":"Weifeng","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,13]]},"reference":[{"issue":"1","key":"e_1_2_12_2_1","first-page":"S229","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: Nuclear hormone receptors","volume":"176","author":"Alexander S. 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