{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T00:05:53Z","timestamp":1793664353960,"version":"4.5.1"},"reference-count":124,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"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>Sepsis is a life\u2212threatening organ dysfunction caused by a dysregulated host response to infection and remains a leading cause of death worldwide. Hyperlactatemia, a hallmark metabolic disorder in sepsis, has recently been recognized as an epigenetic modulator via lysine lactylation. This Review synthesizes the evolving understanding of lactate\u2014from a prognostic biomarker to a pathogenic mediator and, most recently, to an epigenetic modulator through lysine lactylation (Kla). Sepsis induces persistent Warburg\u2212like glycolytic reprogramming in immune and parenchymal cells, generating lactate that not only serves as a metabolic fuel but also accumulates to drive covalent histone and non\u2212histone Kla. Rather than merely indicating tissue hypoxia, this lactate surge directly remodels transcriptional and metabolic programs via both lactyl\u2212CoA\u2212dependent (p300\/CBP, KAT2B) and lactyl\u2212CoA\u2212independent (AARS1\/2) lactylation pathways. We dissect the emerging regulatory network of Kla in sepsis, including validated \u201cwriters\u201d and \u201cerasers\u201d, as well as potential writers and erasers awaiting validation in sepsis models, and map their cell type\u2013specific and substrate\u2212specific effects on acute lung injury, cardiomyopathy, acute kidney injury, and vascular dysfunction. The identical lactylation mark\u2014exemplified by H3K18la\u2014exhibits a context\u2212dependent duality, being protective in macrophages yet pathogenic in alveolar or tubular epithelia. This complexity underscores the urgent need for precision\u2212oriented therapeutic strategies. We further explore how lactate and Kla shape the immunopathological landscape of sepsis by modulating macrophage polarization, trained immunity, neutrophil extracellular trap (NET) formation, and T\u2212cell dysfunction, and we compare these effects with the relatively more uniform immunosuppressive role of lactylation in cancer. Finally, we map the currently known landscape of both histone and non\u2212histone Kla across the various stages of sepsis, thereby providing new avenues for mechanism\u2212based therapies in sepsis and other inflammation\u2212associated disorders.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1900179","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T10:43:05Z","timestamp":1786444985000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Lactate and lactylation in sepsis: regulation of immune-metabolic crosstalk and organ injury"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhiwang","family":"Li","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The First People\u2019s Hospital of Chenzhou, Medical Education Center of Jinan University","place":["Guangzhou, China"]},{"name":"Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Jie","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, The First People\u2019s Hospital of Chenzhou, Hengyang Medical Collage, University of South China","place":["Chenzhou, China"]},{"name":"Department of Emergency Medicine, The First People\u2019s Hospital of Chenzhou, Hunan University of Chinese Medicine","place":["Chenzhou, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingui","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First People\u2019s Hospital of Chenzhou, The First Clinical College, Xiangnan University","place":["Chenzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Jie","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First People\u2019s Hospital of Chenzhou, The First Clinical College, Xiangnan University","place":["Chenzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Yan","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of 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