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We hypothesized that excessive mitochondrial reactive oxygen species (mtROS) production through reverse electron transfer (RET) at mitochondrial complex I contributes to septic myocardial injury and that metformin, a clinically used inhibitor of mitochondrial complex I, protects the myocardium by inhibiting this process. In lipopolysaccharide-stimulated H9C2 cardiomyocytes and cecal ligation and puncture-induced septic rats, sepsis was characterized by an elevated mitochondrial membrane potential, accompanied by succinate accumulation, an increased NADH\/NAD+ ratio, and impaired downstream electron transport. These metabolic changes established favorable conditions for RET-mediated mtROS generation. Metformin inhibited complex I activity and selectively suppressed RET-mediated mtROS generation without increasing ROS production associated with forward electron transport (FET). This effect was accompanied by attenuated inflammatory responses and apoptosis. In septic rats, metformin preserved cardiac function and alleviated myocardial oxidative stress and injury. Overall, these results suggest that RET at mitochondrial complex I represents a potential therapeutic target in SICM and support the use of metformin as a promising strategy for preventing and treating septic myocardial dysfunction.<\/jats:p>","DOI":"10.3390\/biology15151267","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T01:43:27Z","timestamp":1785721407000},"page":"1267","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metformin Attenuates Sepsis-Induced Cardiomyopathy via Inhibition of Reverse Electron Transfer at Mitochondrial Complex I"],"prefix":"10.3390","volume":"15","author":[{"given":"Nannan","family":"He","sequence":"first","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"},{"name":"Department of Critical Care Medicine, Lanzhou University Second Hospital, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Lanzhou University Second Hospital, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannian","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Gansu Province Hospital of TCM, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9046-3142","authenticated-orcid":false,"given":"Chao","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China"},{"name":"State Key Laboratory of Heavy Ion Science and Technology, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China"},{"name":"State Key Laboratory of Heavy Ion Science and Technology, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1048-2758","authenticated-orcid":false,"given":"Xiongxiong","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China"},{"name":"State Key Laboratory of Heavy Ion Science and Technology, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiling","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Lanzhou University Second Hospital, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wei","sequence":"additional","affiliation":[{"name":"Gansu Provincial Maternity and Child-Care Hospital\/Gansu Provincial Center Hospital, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7180-639X","authenticated-orcid":false,"given":"Bing","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute for Radiological Science, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2030-0156","authenticated-orcid":false,"given":"Jian","family":"Liu","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"},{"name":"Gansu Provincial Maternity and Child-Care Hospital\/Gansu Provincial Center Hospital, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1093\/eurheartj\/ehaf980","article-title":"Oestrogen-related receptor \u03b3 in sepsis-induced cardiomyopathy: Role of cardiomyocyte subtype conversion","volume":"47","author":"Yang","year":"2026","journal-title":"Eur. 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