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A mouse model of type 2 diabetes was established through intraperitoneal injection of streptozotocin, after which sepsis was induced by cecal ligation and puncture. For in vitro studies, RAW264.7 macrophages and bone marrow\u2013derived macrophages were exposed to high glucose and lipopolysaccharide. Molecular docking was employed to examine potential binding between dapagliflozin and APOC1. Organ pathology in lung, liver, and kidney was evaluated using hematoxylin and eosin staining and biochemical assay kits. Expression levels of APOC1, HMGB1, TLR4, and macrophage M1\/M2 markers were analyzed via immunohistochemistry and immunofluorescence. Inflammatory cytokine levels were quantified with enzyme-linked immunosorbent assay. The SGLT2 inhibitor dapagliflozin effectively alleviated lung, liver, kidney injury and dysfunction and reduced inflammatory responses in diabetic mice with sepsis. The treatment also decreased inflammatory cytokine levels in the high glucose\/lipopolysaccharide\u2013stimulated cellular model. Furthermore, dapagliflozin treatment significantly increased the levels of M2 macrophage markers in both in vivo and in vitro models. Mechanistically, dapagliflozin was found to target, bind to, and downregulate APOC1 expression. Further investigations revealed that APOC1 promotes macrophage M1 polarization via the APOC1\/HMGB1\/TLR4 axis, an effect reversed by dapagliflozin. The SGLT2 inhibitor dapagliflozin ameliorates organ damage and inflammation in sepsis with diabetes by promoting macrophage M2 polarization through inhibition of the APOC1\/HMGB1\/TLR4 axis.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag240","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T14:32:36Z","timestamp":1790433156000},"source":"Crossref","is-referenced-by-count":0,"title":["Mechanism of SGLT2 inhibitors in improving immune imbalance in diabetic mice with sepsis via regulating macrophage M2 polarization through the APOC1\/HMGB1\/TLR4 axis"],"prefix":"10.1093","volume":"215","author":[{"given":"TingTing","family":"You","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou 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