{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:10:29Z","timestamp":1778217029397,"version":"3.51.4"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Patients with diabetic sepsis exhibit a paradoxical state characterised by persistently elevated inflammatory cytokines and severely impaired antigen presentation, with substantially elevated mortality rates compared to non-diabetic patients. This review assesses the strength of evidence for lactate-epigenetic-immune dysfunction. Immune cells from diabetic patients exhibit basal glycolytic activity 2\u20133 times higher than healthy controls. Blood lactate levels rise markedly during sepsis, exceeding 10 mmol\/L in critically ill patients\u201450-80% higher than non-diabetics. Hyperlactataemia states have been associated with activation of GPR81 receptors and induction of lactylation at histone H3K18. This modification selectively activates inflammatory genes while suppressing antigen-presentation pathways, thereby providing a molecular basis for the paradoxical coexistence of inflammation and immunosuppression observed clinically. Preliminary clinical studies (n = 48) demonstrate a correlation between H3K18la levels and disease severity (r = 0.63). In addition, lactate clearance of &amp;lt;30% within 6 hours is associated with poor prognosis. Current therapeutic evidence remains limited: dichloroacetic acid reduces serum lactate by 20-30% but shows no proven survival benefit; GPR81 modulators remain in development; GM-CSF may increase HLA-DR expression but demonstrates inconsistent effects on infection and mortality. This review identifies three potential therapeutic targets: metabolic regulation to reduce lactate production, intervention in the GPR81-H3K18la signalling axis, and personalised therapy based on immune phenotypes. However, these strategies require validation through high-quality clinical trials.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1735359","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T04:32:47Z","timestamp":1778214767000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcending metabolic acidosis: lactate as an epigenetic signal reprogramming diabetes-sepsis immunity"],"prefix":"10.3389","volume":"17","author":[{"given":"Xin","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liu","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Behavioural Science and Health, University College London","place":["London, United 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