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Meanwhile, whether and how the glycolytic pathway was involved in such IFN-I responses in human SLE remain unclear. In this study, we found that monocytes from SLE patients exerted robust IFN-I generation and elevated level of cytosolic mtDNA. Transfection of mtDNA into THP-1 macrophages was efficient in inducing IFN-I responses, together with the strong glycolytic pathway that promoted lactate production, mimicking the SLE phenotype. Blockade of lactate generation abrogated such IFN-I responses and, vice versa, exogenous lactate enhanced the IFN-I generation. Mechanistically, lactate promoted the lactylation of cGAS, which inhibited its binding to E3 ubiquitination ligase MARCHF5, blocking cGAS degradation and leading to strong IFN-I responses. In accordance, targeting lactate generation alleviated disease development in humanized SLE chimeras. Collectively, cytosolic mtDNA drives metabolic adaption toward the glycolytic pathway, promoting lactylation of cGAS for licensing IFN-I responses in human SLE and thereby assigning the glycolytic pathway as a promising therapeutic target for SLE.<\/jats:p>","DOI":"10.4049\/jimmunol.2300758","type":"journal-article","created":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T13:23:50Z","timestamp":1722605030000},"page":"795-807","source":"Crossref","is-referenced-by-count":50,"title":["Mitochondrial DNA Programs Lactylation of cGAS to Induce IFN Responses in Patients with Systemic Lupus Erythematosus"],"prefix":"10.1093","volume":"213","author":[{"given":"Juan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Lanzhou University Second Hospital , Lanzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyan","family":"Ji","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University , Suzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengdi","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University , Suzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zheng","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University , Suzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0542-0349","authenticated-orcid":false,"given":"Zhenke","family":"Wen","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University , Suzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haili","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Lanzhou University Second Hospital , Lanzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,8,2]]},"reference":[{"key":"2025012305152150700_r1","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1016\/S0140-6736(19)30237-5","article-title":"Management strategies and future directions for systemic lupus erythematosus in adults","volume":"393","author":"Durcan","year":"2019","journal-title":"Lancet"},{"key":"2025012305152150700_r2","doi-asserted-by":"crossref","first-page":"ITC81","DOI":"10.7326\/AITC202006020","article-title":"Systemic lupus erythematosus","volume":"172","author":"Kiriakidou","year":"2020","journal-title":"Ann. 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