{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:54:36Z","timestamp":1791665676408,"version":"4.3.4"},"reference-count":65,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T00:00:00Z","timestamp":1713744000000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005145","name":"Basic Research Program of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20221298"],"award-info":[{"award-number":["BK20221298"]}],"id":[{"id":"10.13039\/501100005145","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2022M721680"],"award-info":[{"award-number":["2022M721680"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Spinal cord injury (SCI)\u2010induced neuroinflammation and oxidative stress (OS) are crucial events causing neurological dysfunction. Aconitate decarboxylase 1 (ACOD1) and its metabolite itaconate (Ita) inhibit inflammation and OS by promoting alkylation of Keap1 to induce Nrf2 expression; however, it is unclear whether there is another pathway regulating their effects in inflammation\u2010activated microglia after SCI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Adult male C57BL\/6 <jats:italic>ACOD1<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>\u00a0mice and their wild\u2010type (WT) littermates were subjected to a moderate thoracic spinal cord contusion. The degree of neuroinflammation and OS in the injured spinal cord were assessed using qPCR, western blot, flow cytometry, immunofluorescence, and trans\u2010well assay. We then employed immunoprecipitation\u2010western blot, chromatin immunoprecipitation (ChIP)\u2010PCR, dual\u2010luciferase assay, and immunofluorescence\u2010confocal imaging to examine the molecular mechanisms of ACOD1. Finally, the locomotor function was evaluated with the Basso Mouse Scale and footprint assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both in vitro and in vivo, microglia with transcriptional blockage of ACOD1 exhibited more severe levels of neuroinflammation and OS, in which the expression of p62\/Keap1\/Nrf2 was down\u2010regulated. Furthermore, silencing ACOD1 exacerbated neurological dysfunction in SCI mice. Administration of exogenous Ita or 4\u2010octyl itaconate reduced p62 phosphorylation. Besides, ACOD1 was capable of interacting with phosphorylated p62 to enhance Nrf2 activation, which in turn further promoted transcription of ACOD1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Here, we identified an unreported ACOD1\u2010p62\u2010Nrf2\u2010ACOD1 feedback loop exerting anti\u2010inflammatory and anti\u2010OS in inflammatory microglia, and demonstrated the neuroprotective role of ACOD1 after SCI, which was different from that of endogenous and exogenous Ita. The present study extends the functions of ACOD1 and uncovers marked property differences between endogenous and exogenous Ita.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>ACOD1 attenuated neuroinflammation and oxidative stress after spinal cord injury.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>ACOD1, not itaconate, interacted with p\u2010p62 to facilitate Nrf2 expression and nuclear translocation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Nrf2 was capable of promoting ACOD1 transcription in microglia.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1661","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T07:50:46Z","timestamp":1713772246000},"source":"Crossref","is-referenced-by-count":36,"title":["ACOD1, rather than itaconate, facilitates p62\u2010mediated activation of Nrf2 in microglia post spinal cord contusion"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6431-9008","authenticated-orcid":false,"given":"Zhanyang","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Orthopedics Taizhou School of Clinical Medicine Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University  Taizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery Nantong First People's Hospital The Second Affiliated Hospital of Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Taizhou School of Clinical Medicine Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University  Taizhou China"},{"name":"Postgraduate School Dalian Medical University  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