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However, the precise mechanisms by which elevated itaconate levels alter macrophage function are not clear. Our hypothesis is itaconate affects macrophage function through some uncertain mechanism. Based on this, we established a transcriptional and proteomic signature of macrophages stimulated by itaconate and identified the pathways of IL\u20101\u03b2 secretion and altered iron metabolism. Consistently, the effect of IRG1 deficiency on IL\u20101\u03b2 secretion and iron metabolism was confirmed in IRG1 knockout THP\u20101 cell lines. Several common inhibitors and other compounds were used to examine the molecular mechanisms involved.\u00a0Only cysteine and antioxidants (catechin hydrate) could inhibit caspase\u20101 activation and IL\u20101\u03b2 secretion in itaconate\u2010stimulated macrophages. We further found that aconitase activity was decreased by itaconate stimulation. Our results demonstrate the counteracting effects of overexpression of mitochondrial aconitase (ACO2,\u00a0a tricarboxylic acid\u00a0cycle enzyme) or cytosolic aconitase (ACO1, an iron regulatory protein) on IL\u20101\u03b2 secretion and altered iron metabolism. Both enzyme activities were inhibited by itaconate because of iron\u2010sulfur (Fe\u2010S)\u00a0cluster destruction. Our findings indicate that the immunoregulatory functions of IRG1 and itaconate in macrophages are stressful Fe\u2010S cluster of aconitases disrupting and iron metabolism rebalancing.<\/jats:p>","DOI":"10.1096\/fj.202100726rr","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T14:44:20Z","timestamp":1632235460000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Itaconate regulates macrophage function through stressful iron\u2010sulfur cluster disrupting and iron metabolism rebalancing"],"prefix":"10.1096","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3034-5179","authenticated-orcid":false,"given":"Xing","family":"Liu","sequence":"first","affiliation":[{"name":"Tianjin Key Laboratory of Ionic\u2010Molecular Function of Cardiovascular Disease Department of Cardiology Tianjin Institute of Cardiology The Second Hospital of Tianjin Medical University Tianjin 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