---
title: "Lactate and lactylation in sepsis: immune–metabolic crosstalk and organ injury"
id: "frontiers-in-immunology-15-lactate-and-lactylation-in-sepsis-regulation-of-immune-metabolic-crosstalk-and"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-15-lactate-and-lactylation-in-sepsis-regulation-of-immune-metabolic-crosstalk-and"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1900179"
published_at: "2026-08-11T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Lactate and lactylation in sepsis: immune–metabolic crosstalk and organ injury
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1900179)
- **Published At:** 2026-08-11T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Source metadata available: article title, journal (Frontiers in Immunology), category (Infectious Disease) and URL were present in the supplied source. The listed title references **lactate**, **lactylation**, and **sepsis**. - The supplied SOURCE JINA BODY contained only website navigation and journal site links; the full article text, abstract, figures, methods, results, and conclusions were not included in the source provided. - No study data, experimental details, patient populations, mechanistic findings, or clinical recommendations were present in the supplied content; therefore no article-specific facts could be extracted or summarized. - Because the body text was missing, detailed discussion of regulation of immune–metabolic crosstalk or organ injury related to lactate/lactylation in sepsis could not be reproduced from the source. - The only actionable information in the source is the journal name and the article URL; readers should retrieve the full article from Frontiers in Immunology or the provided DOI/URL to access primary findings, methods, and conclusions. - Any interpretation, mechanism summaries, treatment implications, or data points are not reported in the supplied source and must not be inferred or invented from outside knowledge.
## Clinical Analysis & Structured Key Points
Frontiers | Lactate and lactylation in sepsis: regulation of immune-metabolic crosstalk and organ injury REVIEW article Front. Immunol. , 11 August 2026 Sec. Systems Immunology Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1900179 Published in Frontiers in Immunology Systems Immunology 7 impact factor 11.3 citescore Editor & Reviewers Edited by K M Konda Mani Saravanan Reviewed by Y L Yajie Liao H D Hanqiang Deng Outline Figures and Tables Figure 1 View in article Figure 2 View in article Table 1 Validated and putative lysine lactylation ‘writers’ in sepsis. View in article Table 2 Validated and putative lysine lactylation ‘erasers’ in sepsis. View in article Table 3 Landscape of protein lactylation modifications across different cell types and systems in sepsis. View in article Table 4 Systematic comparison of lysine lactylation modifications between sepsis and cancer. View in article REVIEW article Front. Immunol. , 11 August 2026 Sec. Systems Immunology Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1900179 Lactate and lactylation in sepsis: regulation of immune-metabolic crosstalk and organ injury Z L Zhiwang Li 1,2 † W G Wan-Jie Gu 2 † T L Tao Li 3,4 † X D Xingui Dai 5 X D Xiang-Jie Duan 2 F Y Feng Yang 5 H Y Hai-Yan Yin 2 ‡ * Z Z Zhiming Zhang 1,2 ‡ * P L Peiyu Li 1,6 ‡ * 1. Department of Anesthesiology, The First People’s Hospital of Chenzhou, Medical Education Center of Jinan University, Guangzhou, China 2. Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University, Guangzhou, China 3. Department of Emergency Medicine, The First People’s Hospital of Chenzhou, Hengyang Medical Collage, University of South China, Chenzhou, China 4. Department of Emergency Medicine, The First People’s Hospital of Chenzhou, Hunan University of Chinese Medicine, Chenzhou, Hunan, China 5. Department of Critical Care Medicine, The First People’s Hospital of Chenzhou, The First Clinical College, Xiangnan University, Chenzhou, China 6. Department of Gastroenterology, The First People’s Hospital of Chenzhou, Chenzhou, China See more Article metrics View details Abstract 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. Background Sepsis is clinically defined as life−threatening organ dysfunction caused by a dysregulated host response to infection. Globally, an estimated 48.9 million new cases occurred in 2017, accounting for 19.7% of all deaths worldwide. The pathophysiology of sepsis involves a complex interplay between excessive inflammation (the “cytokine storm”) ( 1 ), immune paralysis ( 1 , 2 ), coagulopathy ( 3 ), tissue hypoxia, metabolic disorders ( 1 ), and neuroendocrine dysregulation ( 4 ). These systemic alterations can induce multiple organ dysfunctions ( 5 ), including sepsis−induced acute lung injury (ALI/ARDS) ( 6 ), acute kidney injury (AKI) ( 7 ), acute liver injury ( 8 ), sepsis−associated intestinal dysfunction ( 9 ), sepsis−associated coagulopathy ( 3 ), septic cardiomyopathy ( 10 ), and sepsis−associated encephalopathy (SAE) ( 11 ). Elevated blood lactate level is a hallmark of sepsis and correlates tightly with disease severity and mortality ( 12 – 14 ). For decades, hyperlactatemia in sepsis was attributed exclusively to hypoxic anaerobic glycolysis; On this basis, lactate has been used as a biomarker for assessing tissue perfusion and prognosis ( 15 ), forming the basis of early goal−directed therapy centered on lactate clearance ( 16 ). However, recent studies have revealed an active pathological role of lactate in sepsis ( 17 ). It has been shown that under conditions without overt hypoxia, various immune cells in sepsis (e.g., macrophages, dendritic cells, T cells) undergo metabolic reprogramming toward aerobic glycolysis (the Warburg effect), thereby generating large amounts of lactate ( 18 ). This metabolic shift not only responds to hypoxia but also reflects mitochondrial dysfunction and hyperadrenergic stimulation ( 19 ). For example, in resuscitated experimental sepsis models, although enhanced aerobic metabolism and preserved mitochondrial function are observed, the mitochondrial reserve capacity declines early in sepsis and is considered a major contributor to lactate production ( 20 ). Accumulating evidence indicates that hyperlactatemia in sepsis is not merely a marker of oxygen debt but results from inflammation−associated enhanced aerobic glycolysis (Warburg−like effect) in immune cells ( 21 ). This metabolic reprogramming is essential for supporting the biosynthetic demands and effector functions of activated macrophages, dendritic cells, and T cells – a central concept in immunometabolism ( 22 ). Beyond its role as a metabolic intermediate, lactate also acts as a signaling molecule (e.g., activating the NLRP3 inflammasome) that influences cell function ( 23 ). Critically, lactate can also serve as a substrate to directly participate in a novel protein post−translational modification – lactylation – thereby directly linking metabolic alterations to epigenetic regulation ( 24 ). Lactylation profoundly changes protein structure and function and plays a key role in the septic environment, revealing a complex feedback loop between metabolic reprogramming and lactylation ( 24 ). In sepsis, aberrant lactate accumulation drives hyperlactylation, which has been shown to participate in NLRP3 inflammasome activation, pyroptosis, and organ injury ( 23 ). Given the critical role of lactate in sepsis, clinicians have increasingly recognized the deleterious effects of lactate on the body. A growing number of clinical studies have focused on the impact of lactate clearance rate on the prognosis of septic patients ( 16 , 25 , 26 ). However, hemofiltration only transiently removes lactate from the peripheral blood and cannot eliminate lactate accumulated within immune cells. In light of the rapidly expanding body of lactate-related research, a systematic synthesis and summary are urgently needed. This review comprehensively integrates current knowledge of lactate metabolism and lactylation in sepsis, systematically delineates the molecular mechanisms by which lactate contributes to sepsis progression, and discusses therapeutic strategies targeting lactate in sepsis, thereby clarifying the potential value of lactate in clinical application and prognosis improvement ( Figure 1 ). Specifically, this review aims to systematically elucidate the evolution of lactate’s role in sepsis from a “metabolic waste product” to a “pathological mediator” and further to an “epigenetic regulator”, deeply dissect the molecular mechanisms by which it exacerbates immunosuppression and mediates organ injury, and critically discuss the core regulatory network and pathological significance of lactylation as an emerging field, thereby providing a comprehensive theoretical framework for the future development of precision therapeutic strategies based on lactate metabolism and epigenetic regulation. Figure 1 Mechanism by which altered lactate metabolism affects organ function through lysine lactylation (epigenetic modification) in sepsis. Hyperlactatemia and clinical outcomes in sepsis: an updated overview Large retrospective database studies have firmly established the association between hyperlactatemia and adverse outcomes in sepsis. In an analysis of 4,199 elderly patients from the MIMIC−IV database, each 1 mmol/L increase in lactate was associated with an OR of 1.23 (95% CI 1.18–1.28) for 28−day mortality. A non−linear relationship was observed, with a turning point at 5.7 mmol/L ( 27 ). Using the eICU database (n=10,724), in−hospital mortality increased stepwise from 13% (lactate 2 mmol/L as one of the core diagnostic criteria for septic shock ( 32 , 33 ). Collectively, these studies indicate that an elevated initial lactate level is a key quantifiable indicator for assessing sepsis severity and mortality risk. However, correlation does not equal causation. Randomized trials aimed at lowering lactate (e.g., with dichloroacetate, DCA) have not improved outcomes; indeed, Stacpoole et al. reported increased mortality at 24 hours, 72 hours, and 30 days in septic patients receiving DCA ( 34 ). Therefore, although lactate is an excellent prognostic marker, simply targeting lactate levels is unlikely to confer benefit. This paradox has fueled the search for active pathogenic roles of lactate – a role now linked to lysine lactylation. Metabolic sources and transport of lactate in sepsis Under physiological conditions, lactate originates mainly from anaerobic glycolysis in skeletal muscle, brain, and erythrocytes. In sepsis, lactate production increases markedly through both hypoxia−dependent and hypoxia−independent pathways. The classic view holds that tissue hypoperfusion and microcirculatory dysfunction in septic shock lead to enhanced anaerobic glycolysis ( 35 ). This mechanism plays a major role in advanced or hypoperfusion−associated sepsis. However, studies have shown that hyperlactatemia in sepsis is often dissociated from tissue hypoperfusion, and that serum lactate levels can remain persistently elevated even after oxygen delivery has been restored or augmented, suggesting the presence of hypoxia-independent lactate production pathways ( 36 , 37 ). The concept of “aerobic glycolysis” (the Warburg effect) – initially described in tumor metabolism – has been extended to activated immune cells. LPS−stimulated macrophages exhibit markedly increased glycolytic activity ( 38 ), including enhanced glucose uptake, elevated lactate production, and accelerated extracellular acidification rate ( 38 , 39 ). This metabolic shift is not passively triggered by hypoxia but is an active reprogramming of cells in response to infection and inflammation, aimed at rapid ATP generation and biosynthetic precursor supply, but it also leads to substantial lactate accumulation ( 40 ). Altered pyruvate metabolism is central to this process: as the key metabolic node connecting glycolysis to mitochondrial oxidative phosphorylation, dysregulation of pyruvate pathways directly promotes lactate generation ( 40 ). This metabolic reprogramming is finely regulated by signaling pathways such as HIF−1α and mTOR ( 41 ). Under hypoxic conditions, hypoxia−inducible factor−1α (HIF−1α) is stabilized and upregulates multiple glycolysis−related genes (e.g., HK2, PDK1), enhancing glycolytic flux ( 42 ). Notably, even in the absence of overt hypoxia in sepsis, LPS activates the NF−κB pathway through TLR4, and NF−κB family members mediate HIF−1α upregulation ( 43 ). HIF−1α induces PKM2 dimerization via the ESM1−PKM2 axis, thereby promoting the Warburg effect ( 44 ). Inflammatory signals (e.g., via the PI3K/Akt pathway) can also activate HIF−1α and induce aerobic glycolysis ( 45 ). Palsson−McDermott et al. demonstrated that PKM2 exists as a monomer/dimer in macrophages and, upon binding to Hif−1α, promotes IL−1β transcription and glycolytic metabolism ( 39 ). In addition, other pro−inflammatory cytokines, including IL−2, IL−3, IL−7, interferon−γ (IFN−γ), and tumor necrosis factor−α (TNF−α), enhance glucose metabolism and lactate production ( 46 – 48 ). Besides immune cells, endothelial cells in sepsis also rely heavily on glycolysis for energy. Because endothelial cells have low mitochondrial content, their ATP generation during immune responses depends mainly on glycolysis, further exacerbating lactate accumulation ( 49 ). Meanwhile, sepsis−induced mitochondrial dysfunction and downregulation of pyruvate dehydrogenase (PDH) activity inhibit oxidative phosphorylation and the tricarboxylic acid (TCA) cycle, not only reducing ATP production but also diverting pyruvate toward lactate generation, creating a vicious cycle of increased lactate production and reduced lactate clearance ( 50 ). Lactate is transported across cell membranes by the monocarboxylate transporter (MCT) family (notably MCT1 and MCT4) ( 51 ). MCT1 is ubiquitously expressed, has a high affinity for lactate, and mediates lactate uptake under physiological concentrations. MCT4 is induced by HIF−1α and is mainly responsible for lactate efflux from highly glycolytic cells ( 52 ). Importantly, this shuttle also occurs intracellularly: cytosolic lactate enters the mitochondria via MCT1 (or as−yet−unidentified mechanisms) on the inner mitochondrial membrane and is converted back to pyruvate by mitochondrial LDHA/B, providing a direct carbon source for the TCA cycle ( 53 ). Studies on the regulation of lactate transport by MCT1 and MCT4 in sepsis remain limited. It has been shown that MCT1 plays a key role in lactate−mediated inhibition of ZBP1−PANoptosis ( 54 ). Another study indicated that LPS downregulates MCT1 expression in mouse alveolar epithelial cells, leading to lactate transport impairment, lactate accumulation, and ultimately promoting EMT and pulmonary fibrosis ( 55 ). These findings suggest that the expression level and functional status of MCTs are central links connecting sepsis−induced metabolic disturbances with immune−inflammatory dysregulation. Regulation of lactate homeostasis in sepsis Lactate clearance occurs mainly through gluconeogenesis (Cori cycle) and direct oxidation in the liver and kidneys ( 56 – 58 ). In sepsis, hepatic and renal dysfunction can impair lactate clearance, leading to persistent hyperlactatemia ( 59 – 63 ). Notably, in inflammatory macrophages, the combination of GM-CSF and IFNγ upregulates the expression of mitochondrial phosphoenolpyruvate carboxykinase (PCK2), which drives the conversion of lactate into glycogen. This process represents a compensatory metabolic adaptation that facilitates lactate clearance and sustains macrophage function within nutrient-deprived microenvironments ( 64 ). In sepsis, liver-nfiltrating monocyte-derived macrophages (MDMs) exhibit significant mitochondrial dysfunction, characterized by reduced activities of key tricarboxylic acid (TCA) cycle enzymes, including isocitrate dehydrogenase (IDH) and succinate dehydrogenase (SDH), along with impaired oxidative phosphorylation (OXPHOS), which in turn compromises their immunometabolic functions ( 65 ). This metabolic disturbance may further affect the hepatic immune microenvironment, indirectly aggravating hepatocyte injury, forming a vicious cycle of increased lactate production and decreased clearance. Clinical observations also confirm that serum lactate concentration correlates positively with SOFA/qSOFA scores, suggesting that hyperlactatemia is closely associated with the severity of organ dysfunction in sepsis ( 66 ). Downregulation of PDH activity is another important cause of lactate accumulation. PDH activity in peripheral blood mononuclear cells of septic patients is significantly reduced, and its activity correlates with patient survival. Baseline lactate level correlates negatively with PDH activity ( 40 ). Sepsis inhibits PDH activity by activating pyruvate dehydrogenase kinase (PDHK), further exacerbating lactate accumulation ( 67 ). Therefore, maintaining lactate homeostasis requires not only controlling excessive production but also preserving the clearance functions of the liver and kidneys. Lactate as a metabolic fuel and its metabolic diversion toward lactylation Despite its reputation as a “metabolic waste product”, lactate is actually a preferred oxidative fuel for many tissues. Sepsis-associated hyperlactatemia has also been regarded as an adaptive phenomenon that enhances bioenergetic efficiency in the brain and heart through lactate oxidation ( 68 ). Even in the presence of glucose, lactate serves as an efficient energy source for neurons ( 69 ). Further studies have demonstrated that inhibition of the neuronal lactate transporter MCT2 reverses the depolarization (high K+)-induced enhancement of oxidative phosphorylation and the concomitant decrease in extracellular lactate, suggesting that neurons rely on MCT2-mediated lactate uptake to support oxidative metabolism under activated conditions ( 70 ). Although the above views have not been fully validated in the field of sepsis research, the collective evidence suggests that during inflammation-induced hypoglycemia or tissue hypoxia, lactate may serve as a key energy substrate for the heart, brain, and immune cells. Notably, the efficiency with which lactate serves as an oxidative substrate directly dictates its availabilit
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