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Acute Myeloid Leukemia Research / Cancer, Hypoxia, and Metabolism / Immune Cells in Cancer · Journal article
Frontiers in Immunology · August 11, 2026
Raises a question worth testing. It does not answer one.
This narrative review maps the emerging role of lactate and lysine lactylation in sepsis pathophysiology, proposing that lactate acts not merely as a biomarker but as an epigenetic modulator that remodels immune and parenchymal cell function through histone and non-histone lactylation. The authors identify validated and candidate lactylation 'writers' and 'erasers' and highlight cell-type and context-dependent effects on organ injury, but call for validation of many mechanisms and development of precision-oriented therapeutic strategies rather than reporting definitive empirical findings.
Journal article. Sepsis patients and sepsis models (preclinical); immune and parenchymal cells..
Hyperlactatemia in sepsis drives lysine lactylation (Kla) of histone and non-histone proteins via both lactyl-CoA-dependent (p300/CBP, KAT2B) and lactyl-CoA-independent (AARS1/2) pathways. The lactylation mark H3K18la exhibits context-dependent duality: protective in macrophages yet pathogenic in alveolar or tubular epithelia. Lactate and Kla modulate macrophage polarization, trained immunity, neutrophil extracellular trap formation, and T-cell dysfunction in sepsis immunopathology.
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This review identifies lactate and lactylation as potential therapeutic targets in sepsis but emphasizes that cell-type and context-dependent effects require precision medicine approaches; the mechanisms and candidate regulators described remain largely unvalidated and warrant further clinical translation.
This is a narrative review synthesizing mechanistic understanding of lactate and lysine lactylation in sepsis pathophysiology, raising questions about therapeutic targets rather than reporting empirical evidence from a primary study.
This review identifies lactate and lactylation as potential therapeutic targets in sepsis but emphasizes that cell-type and context-dependent effects require precision medicine approaches; the mechanisms and candidate regulators described remain largely unvalidated and warrant further clinical translation.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
What is missing. This record has no reported figures. That is a gap in the analysis, not a judgement about the study.
Sepsis is a life−threatening 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—from a prognostic biomarker to a pathogenic mediator and, most recently, to an epigenetic modulator through lysine lactylation (Kla). Sepsis induces persistent Warburg−like 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−histone Kla. Rather than merely indicating tissue hypoxia, this lactate surge directly remodels transcriptional and metabolic programs via both lactyl−CoA−dependent (p300/CBP, KAT2B) and lactyl−CoA−independent (AARS1/2) lactylation pathways. We dissect the emerging regulatory network of Kla in sepsis, including validated “writers” and “erasers”, as well as potential writers and erasers awaiting validation in sepsis models, and map their cell type–specific and substrate−specific effects on acute lung injury, cardiomyopathy, acute kidney injury, and vascular dysfunction. The identical lactylation mark—exemplified by H3K18la—exhibits a context−dependent duality, being protective in macrophages yet pathogenic in alveolar or tubular epithelia. This complexity underscores the urgent need for precision−oriented 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−cell 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−histone Kla across the various stages of sepsis, thereby providing new avenues for mechanism−based therapies in sepsis and other inflammation−associated disorders.
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