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Sudden restoration of blood flow after a period of ischemia triggers a rapid accumulation of reactive oxygen species (ROS) and oxidative stress that promote pathological injury. Macrophage-derived inflammatory responses are also thought to contribute to such injury, but how ROS influences tissue macrophages and their elaboration of inflammatory cytokines in IRI remains poorly understood. In this study, we showed that macrophages mobilize mitochondrial adaptations during reoxygenation, including mitochondrial fission and ubiquitin proteasome system (UPS) flux. Furthermore, the transcription factor Nuclear Factor Erythroid 2 Like 1 (NRF1) is rapidly induced during reoxygenation in response to rising levels of ROS. Induction of NRF1 upregulates ubiquitin proteasome system (UPS) and mitophagy pathways to mediate mitochondrial fusion\/fission dynamics and dampen ROS production, allowing for alleviation of oxidative stress and the inflammatory response. Conversely, the absence of myeloid NRF1 leads to increased ROS, driving enhanced inflammation and kidney injury in a mouse model of IRI. We thus identify macrophage NRF1 as a master regulator of mitochondrial homeostasis, antioxidant defense, and inflammatory responses in IRI.<\/jats:p>","DOI":"10.1038\/s41420-025-02461-5","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T06:53:08Z","timestamp":1747291988000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["NRF1 coordinates mitochondrial adaptations to dampen intracellular ROS and inflammatory responses during ischemia reperfusion"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6874-0121","authenticated-orcid":false,"given":"Jiakun","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guowei","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjiao","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3516-8308","authenticated-orcid":false,"given":"Changhong","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1384-1565","authenticated-orcid":false,"given":"Zhe","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9265-4559","authenticated-orcid":false,"given":"Tiffany","family":"Horng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"2461_CR1","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1016\/j.freeradbiomed.2020.09.011","volume":"160","author":"A Grivei","year":"2020","unstructured":"Grivei A, Giuliani KTK, Wang X, Ungerer J, Francis L, Hepburn K, et al. 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