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Pulmonary microvascular endothelial cells (PMVECs) play a significant role in the development of lung diseases. Aconitate decarboxylase 1 (Acod1) mediates the production of itaconate, and Acod1\/itaconate axis has been reported to play a protective role in multiple diseases. However, the roles of Acod1\/itaconate axis in the PMVECs of obese mice are still unclear.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>mRNA-seq was performed to identify the differentially expressed genes (DEGs) between high-fat diet (HFD)-induced PMVECs and chow-fed PMVECs in mice (|log<jats:sub>2<\/jats:sub> fold change| \u2265 1, <jats:italic>p<\/jats:italic>\u2009\u2264\u20090.05). Free fatty acid (FFA) was used to induce cell injury, inflammation and mitochondrial oxidative stress in mouse PMVECs after transfection with the Acod1 overexpressed plasmid or 4-Octyl Itaconate (4-OI) administration. In addition, we investigated whether the nuclear factor erythroid 2-like 2 (Nrf2) pathway was involved in the effects of Acod1\/itaconate in FFA-induced PMVECs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Down-regulated Acod1 was identified in HFD mouse PMVECs by mRNA-seq.\u00a0Acod1 expression was also reduced in FFA-treated PMVECs. Acod1 overexpression inhibited cell injury, inflammation and mitochondrial oxidative stress induced by FFA in mouse PMVECs. 4-OI administration showed the consistent results in FFA-treated mouse PMVECs. Moreover, silencing Nrf2 reversed the effects of Acod1 overexpression and 4-OI administration in FFA-treated PMVECs, indicating that Nrf2 activation was required for the protective effects of Acod1\/itaconate.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our results demonstrated that Acod1\/Itaconate axis might protect mouse PMVECs from FFA-induced injury, inflammation and mitochondrial oxidative stress via activating Nrf2 pathway. It was meaningful for the treatment of obesity-caused pulmonary microvascular endotheliopathy.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12931-024-02827-w","type":"journal-article","created":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T17:02:05Z","timestamp":1715360525000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Acod1\/itaconate activates Nrf2 in pulmonary microvascular endothelial cells to protect against the obesity-induced pulmonary microvascular endotheliopathy"],"prefix":"10.1186","volume":"25","author":[{"given":"Li","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuhua","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingli","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Ming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2653-1307","authenticated-orcid":false,"given":"Yong","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,10]]},"reference":[{"key":"2827_CR1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.metabol.2018.09.005","volume":"92","author":"YC Chooi","year":"2019","unstructured":"Chooi YC, Ding C, Magkos F. 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