Lactate: elucidating its indispensable role in human health.

Introduction
Lactate has long been viewed as a metabolic waste product, and its production was historically believed to be associated primarily with strenuous exercise or hypoxic conditions [1, 2]. However, this perspective has evolved significantly, with accumulating evidence showing that lactate is continuously produced and utilized even under well-oxygenated conditions in organs like the brain and heart [3].
Structurally, lactic acid consists of three isomers: D-lactic acid, L-lactic acid, and DL-lactic acid, with L-lactic acid being the dominant form in mammals [4]. Lactate is primarily produced via glycolytic metabolism. While this process is often associated with low-oxygen environments, it also occurs under aerobic conditions in metabolically active tissues such as the brain, heart, and resting skeletal muscle, where lactate dehydrogenase (LDH) facilitates the reversible conversion of pyruvate into lactate in the cytoplasm [3, 4]. In addition, glutamine metabolism may also contribute to lactate production in cancer cells. With a better understanding of the “Warburg effect”, it has been found that highly proliferative cells still prefer glycolysis for lactate production even in an aerobic environment [5]. This phenomenon is not restricted to tumor cells but is also manifests itself in a variety of non-neoplastic pathological conditions, such as pulmonary vascular remodeling, cardiac hypertrophy, and multiple sclerosis, and its metabolic inhibitors have shown potential for therapeutic use. This phenomenon is not limited to tumor cells, but also manifests itself in a variety of non-tumor pathological conditions, such as pulmonary vascular remodeling, cardiac hypertrophy, and multiple sclerosis, and its metabolic inhibitors have shown some therapeutic potential [6, 7].
Brooks proposed the theory of the “lactate shuttle”, indicating that lactate can also act as an energy source via oxidative pathways in different organs and cells in an aerobic environment, facilitating metabolic coordination across tissues [8, 9]. Lactate plays a crucial role in maintaining redox homeostasis by regulating the NAD⁺/NADH ratio. After its intracellular production, lactate can enter the circulation via monocarboxylic acid transporters (MCTs) and be further taken up by distal tissues for energy metabolism [10, 11]. Another key mechanism involves lactate acting as a signaling mediator via the G protein-coupled receptor GPR81 (also known as HCAR1). Moreover, the presence of lactate transporters and pannexin-based gap junctions in astrocytes highlights their unique role in central nervous system function [12–14].
While the foundational role of lactate in cellular metabolism has been well-established for years, recent discoveries have significantly expanded our understanding. In 2019, lactylation was identified as a novel post-translational modification (PTM) on both histone and non-histone proteins, establishing a direct link between lactate and gene expression regulation. This lactylation process, catalyzed by ‘writer’ proteins like acetyltransferase p300, and reversible by ‘eraser’ proteins such as histone deacetylases (HDACs), reveals lactate’s role as an epigenetic regulator and intercellular communicator [15].
Furthermore, lactate has emerged as a key player in immune regulation, with evidence pointing to its impact on immune cell function through mechanisms such as receptor signaling via GPR81 and histone lactylation, which are closely linked to its immune-modulatory effects [16]. Additionally, lactate metabolism exert its impact on the development of many diseases, including autoimmune diseases, cardiovascular diseases, and metabolic syndrome [17–19]. It is also increasingly recognized for its role in the microbiome, where it influences gut health and microbial balance, further extending its biological functions [20]. In the tumor microenvironment (TME), lactate even contributes to tumor progression through mechanisms such as immunosuppression, angiogenesis, metastasis promotion and epigenetic reprogramming [21, 22].
This review highlights recent advances in lactate biology, focusing on its multifaceted roles in energy metabolism, immune regulation, gene expression, and disease development across multiple organ systems. Lactate is now recognized not only as a metabolic intermediate but also as a signaling mediator and regulatory molecule that orchestrates diverse physiological and pathological processes through metabolic, immune, and epigenetic mechanisms. In light of these insights, this review further explores emerging therapeutic strategies targeting lactate metabolism, transport, and downstream immune or epigenetic pathways. Throughout this review, we will carefully delineate mechanistic insights derived from experimental models from evidence obtained in clinical settings, thereby providing a clear perspective on the translational path of lactate biology.

Lactate: from byproduct to central metabolite

Lactate production and metabolic origins
Lactate is widely recognized as a key regulator in cellular energy metabolism. Under physiological conditions, its concentration is typically maintained within a narrow range of 0.5 to 2.2 mmol/L. It is distributed and released from all parts of the body (muscle, skin, brain, and intestines). The clearance of lactate is mainly dependent on liver metabolism through Cori cycle while myocytes and kidney cells can also utilize it as the source of energy under specific conditions [23, 24].
Generally speaking, lactate production is typically triggered under hypoxic conditions, when cells shift from aerobic respiration to glycolysis using the same substrate pyruvate. Under aerobic conditions, pyruvate is converted to ATP via mitochondrial oxidation, whereas under hypoxia, it is transformed into lactate by LDH, which also plays a crucial role in gluconeogenesis and lactate biosynthesis [15, 25]. While glycolysis from glucose is the predominant source of lactate under most physiological conditions, certain metabolic contexts utilize alternative precursors. Notably, in some cancer cells under hypoxic conditions or with mitochondrial dysfunction, glutamine metabolism can contribute to lactate production via anaplerotic pathways such as reductive carboxylation [26, 27]. In this setting, glutamine-derived α-ketoglutaric acid (α-KG) is converted to isocitrate and then to citrate through reductive carboxylation, followed by the generation of pyruvate and lactate, providing a pathway for lactate synthesis independent of glucose metabolism [4, 27].
The quantitative impact of glutamine on the overall lactate pool varies significantly depending on the context, and it is typically smaller in comparison to glucose [28]. This is underscored by in vivo isotopic tracing studies in human lung cancers, which, despite revealing that circulating lactate can serve as a major respiratory fuel surpassing glucose in some tumors, simultaneously demonstrated that glucose, instead of glutamine, remains the primary substrate for carboxylation anaplerosis within tricarboxylic acid (TCA) cycle [29]. This highlights that while the glutamine-to-lactate pathway is operational, its overall significance in fuel economy is often secondary to glycolysis-derived carbon. The central role of lactate in systemic energy metabolism is further exemplified by the Cori cycle. Studies have shown that during intense physical activity, a significant portion of glucose production originates from lactate consumed via this cycle. This process not only demonstrates lactate’s function as a key gluconeogenic precursor but also solidifies its position as a central energy carrier, efficiently shuttling carbon between glycolytic and oxidative tissues [30].
Although lactate has been widely accepted as a key fuel source in mitochondrial metabolism, whether it can be directly oxidized in mitochondria is still controversial. Some studies have proposed the concept of mitochondrial lactate oxidation complex (mLOC), comprising mitochondrial LDH (mLDH), MCT1, and CD147, which may mediate the direct entry of lactate into mitochondria for subsequent utilization. Supporters of this model have observed co-localization of these proteins in mitochondrial membranes of oxidative tissues [8, 31]. However, other studies have challenged the presence or functional relevance of mLOC, arguing instead that lactate is likely to first be converted to pyruvate in the cytosol before being imported into mitochondria via the mitochondrial pyruvate carrier (MPC) [32]. Thus, while the lactate-TCA cycle-oxidative phosphorylation (OXPHOS) axis is well supported, whether lactate enters mitochondria directly or is first converted to pyruvate in the cytosol remains uncertain, and the preferred route may vary across different tissue types or metabolic conditions [2].

Lactate as an alternative fuel
L-lactate functions as a key mediator acting as mitochondrial fuel, undergoing conversion to pyruvate and feeding into downstream oxidative metabolic pathways to sustain cellular energy output. This ‘lactate-TCA-OXPHOS’ metabolic axis reveals that lactate is not only a by-product of glycolysis, but also an important mitochondrial fuel for maintaining energy homeostasis in cells, including tumor cells, under fluctuating oxygen conditions [8, 28]. Besides, in skeletal muscles, lactate accumulation alters the NADH/NAD+ ratio in parallel with changes in the ADP/ATP ratio, thereby promoting ongoing oxidative phosphorylation. Similar metabolic responses are observed in brain tissues, suggesting lactate’s extensive role in metabolic regulation across multiple organs and its importance in maintaining redox balance [33].
Additionally, lactate can serve as an important substrate in metabolic activities and provides a supplemental energy source for oxidative metabolism. The NAD+/NADH ratio, as a dominant parameter, reflects fluctuations in intracellular lactate abundance, aligning with regulation by LDH and mitochondrial complexes [34]. LDH modulates lactate-pyruvate interconversion, which is accompanied by the electron shuttle, while mitochondrial complexes maintain oxidative respiration. Interestingly, the activation of the pyruvate dehydrogenase (PDH) complex results in a decrease in the NAD+/NADH ratio, indicating an increase in NADH production. When the demand for NAD+ in oxidative processes exceeds the rate of NAD+ regeneration in mitochondria, metabolic flux shifts toward glycolysis. This dynamic adjustment may subsequently modulate PDH activity [10].

Lactate transportation

Mechanisms of lactate transmembrane
The most representative transporters responsible for both intercellular and intracellular lactate shuttle are MCTs [35]. Monocarboxylate transporters are capable of recognizing a wide range of substrates, including lactate, pyruvate, acetoacetate, and various ketone compounds. Among the identified isoforms, MCT1 through MCT4 have been most extensively examined in terms of their structural features and physiological roles [35, 36]. CD147 functions as an ancillary protein, facilitating the colocalization of MCT1/4 and promoting the membrane trafficking of MCT1 and MCT2 [37]. In preclinical tumor models, MCTs have been demonstrated to play key roles in tumor metabolism by regulating lactate exchange [38].
In addition to their transport functions, MCTs also participate in lactate-mediated signaling. For instance, lactate metabolism has been studied as a modulatory agent to induce specific signaling transduction, and lactate enters the cells through MCTs and engages with GPR81 receptors in an autocrine manner, thereby reducing cAMP generation and modulating the insulin-induced PI3K-AKT pathway [39–41]. Thus, lactate is increasingly recognized as a critical metabolic substrate that intersects with diverse cellular signaling networks [42].

Mechanisms of lactate transport
The mechanisms of lactate transport are primarily regulated by concentration gradients, proton coupling, and transporter expression patterns [8, 43]. Oxidative cells such as those in well-oxygenated tumor regions typically express MCT1, a high-affinity monocarboxylate transporter that promotes lactate uptake for mitochondrial oxidative phosphorylation [35]. Since MCTs function via passive diffusion, lactate transport depends on the existing concentration gradients of both lactate and hydrogen ions across the membrane. Therefore, MCT1 can mediate lactate uptake in oxidative cells where lactate is consumed, but under specific conditions where the intracellular lactate concentration is high, it can also mediate lactate efflux to maintain metabolic homeostasis [35, 44, 45].
Additionally, MCT2 is chiefly responsible for transporting lactate into metabolically active tissues with rich blood supply [46]. For instance, in the central nervous system, astrocyte-secreted lactate flows into neurons through MCT2 as a fuel source, thereby promoting neuronal plasticity [47]. Beyond its role in energy supply, MCT2 (encoded by SLC16A7) has recently drawn attention for its involvement in neurological and neurodegenerative diseases. In the central nervous system, MCT2 is recognized as a high-affinity lactate transporter located on neurons and serves as a key component of the astrocyte-neuron lactate shuttle (ANLS) pathway. Within this pathway, astrocytes export lactate to the extracellular space via MCT1 and MCT4, after which neurons take up lactate through MCT2 and convert it to pyruvate for entry into the TCA cycle to support oxidative metabolism [48, 49]. A growing body of evidence also suggests that dysregulation of the MCT2-mediated lactate shuttle contributes to neuronal metabolic stress and synaptic dysfunction, particularly in neurodegenerative conditions [49–51]. For instance, dysregulation of MCT2-mediated lactate shuttle has been observed in neurological diseases, such as Alzheimer’s disease, suggesting its potential role in neuronal survival and disease progression [52]. Nevertheless, whether similar MCT2-related dysregulation occurs in other neurological disorders remains to be fully established and requires further validation. Moreover, MCT4 is significantly upregulated in cells with dominant glycolytic activity. As a proton-coupled transporter, it facilitates the co-efflux of lactate and protons, thereby eliminating these glycolytic byproducts and helping to maintain intracellular pH homeostasis [53]. This reflects a key implication in malignancies, whose intrinsic environment is highly dependent on glycolysis, as characterized by the Warburg effect. The amplification of MCT1 and MCT4 has been demonstrated in solid tumors and represents a dominant force controlling glycolytic activities [54].
In addition, CD147, also known as basigin or EMMPRIN, is essential for ensuring the proper folding, trafficking, and functionality of MCT1 and MCT4 transporters [55]. Studies have shown that CD147 forms stable, non-covalent complexes with MCT1 and MCT4, serving as an essential chaperone for their proper folding and trafficking to the plasma membrane [36, 56]. CD147 inhibitors lead to intracellular retention of MCT1/4, disrupting lactate transport and intercellular lactate exchange [55].

The “lactate shuttle” theory and tumor metabolic symbiosis
It should be noted that lactate accumulation per se does not directly cause acidification; rather, the proton-coupled transport through MCTs is the main driver of pH alterations observed in the TME [57, 58]. The “lactate shuttle” concept is now recognized as a fundamental mechanism for metabolic coordination and signaling under aerobic conditions. This shuttle operates through several coordinated models. The first is metabolic symbiosis between tumor cells: hypoxic cells export lactate and protons via MCT4, while normoxic neighbors import it via MCT1 for oxidative phosphorylation, thereby optimizing intra-tumoral resource utilization [45]. Further extending this paradigm, the “reverse Warburg effect” describes a stromal-epithelial coupling where cancer-associated fibroblasts (CAFs), under oxidative stress, activate hypoxia-inducible factor 1-alpha (HIF-1α) and release lactate via MCT4, which cancer cells then import via MCT1 to fuel their oxidative metabolism, creating an acidic, lactate-rich niche that supports tumor growth [59].
Beyond its metabolic role, lactate also acts as a signaling molecule by entering vascular endothelial cells via MCT1, where it stabilizes HIF-1α and activates pro-angiogenic pathways such as NF-κB/IL-8, thereby promoting tumor angiogenesis [60–62]. The critical role of this multi-faceted lactate shuttle is underscored by its validation across multiple tumor models (e.g., breast, prostate, osteosarcoma), where elevated MCT4 expression in CAFs is closely associated with enhanced tumor aggressiveness. Based on robust preclinical data across multiple cancer types, targeting MCT1 and MCT4 emerges as a mechanistically rational therapeutic strategy. This is supported by the ongoing clinical development of inhibitors like AZD3965 (MCT1, Phase I), which will ultimately test this hypothesis in human patients [63–69].

Lactate-induced epigenetic modifications

Histone and non-histone lactylation
Lactate production is markedly enhanced when cellular oxygen demand substantially exceeds supply. While the majority of lactate is derived from pyruvate, a fraction may also originate from glutamine decomposition. In addition to the classical L-lactate generated via LDH, alternative pathways contribute to the intracellular lactate pool. For instance, tumor cells are suggested to potentially produce D-lactate through the glyoxalase system [70, 71]. This pathway involves the metabolism of methylglyoxal (MGO) into lactoylglutathione (LGSH) by glyoxalase I (GLO1) with glutathione (GSH), followed by hydrolysis via glyoxalase II (GLO2) to yield D-lactate. It is important to note, however, that the physiological relevance and quantitative contribution of this glyoxalase/MGO-derived pathway to overall lactate metabolism and related lactylation modifications remain to be fully established. Accumulated lactate contributes to cytoplasmic acidosis, prompting cells to activate compensatory mechanisms for exporting excess lactate into the extracellular space and circulation. These dynamic regulatory processes underscore the precision of lactate metabolic control and reflect the complex homeostatic mechanisms governing its metabolism [72].
Lactylation is a coping mechanism in response to lactate accumulation in the matrix. The most ubiquitously exhibited lactylation site is lysine. lysine lactylation (Kla) was elucidated to undergo transfer of lactyl groups from lactyl-CoA. L-lactate has been proposed to form lactyl-CoA, which may serve as a potential donor for enzymatic transfer by p300/CBP to lysine residues of histones, thereby generating Kla. Moreover, under conditions of GLO2 deficiency or LGSH accumulation, non-enzymatic transfer of lactoyl groups to lysine residues may occur, forming a putative modification termed LactoylLys. However, the presence of lactyl-CoA at physiological concentrations has not yet been directly demonstrated, and this pathway remains under debate [73]. It may represent a novel enzymatic signaling pathway; however, this prospect must be rigorously distinguished from the possibility that the signals are merely secondary modifications related to oxidative stress. The definitive establishment of the former necessitates direct validation of key intermediates such as lactyl-CoA [74]. This distinction is critical, as the field encompasses both specific enzymatic modifications and non-enzymatic chemical alterations that can occur under certain metabolic deficiencies or, more problematically, as technical artifacts during experimental procedures. Therefore, future research must prioritize the development and implementation of stringent methodological controls to delineate the precise contributions of enzymatic versus non-enzymatic mechanisms. Unraveling this interplay is paramount for understanding the true physiological and pathophysiological significance of protein lactylation. As summarized in Fig. 1, these distinct lactylation pathways highlight how metabolic intermediates feed directly into post-translational modifications.
Recent studies have highlighted Kla on both histone and non-histone proteins. Histone Kla is metabolically linked to glycolysis-derived lactate and functions predominantly in regulating gene expression through chromatin remodeling [75]. A seminal study by Zhang et al. further demonstrates that histone lactylation is a novel epigenetic mark that stimulates gene transcriptional activity on chromatin in response to elevated intracellular lactate levels, and is particularly prominent during M1-type macrophage polarization. It was shown that histone lactylation differentiates itself from conventional acetylation modifications in terms of temporal dynamics and induces the expression of genes involved in tissue repair, such as Arg1, during the later stages of macrophage activation [15].
In cancer, aberrant histone lactylation is frequently elevated and has been associated with poor prognosis, while functional inhibition of histone Kla has been reported to suppress tumor progression in vitro and in vivo. Mechanistically, recent studies have suggested that histone lactylation may upregulate the expression of the m6A recognition protein YTHDF2, thereby potentially influencing the degradation of oncogene transcripts such as PER1 and TP53 and contributing to tumorigenic processes. These observations provide preliminary evidence for the interplay between histone modifications and RNA epigenetics in cancer progression, although further studies are required to confirm these mechanisms [76].
Given that Kla is distinct with temporal dynamics from histone acetylation, it portraits a blueprint where lactate-modulated histone Kla can be perceived as a response to a surging cellular-lactate concentration owing to external stimulants [15]. Beyond histones, Kla has also been identified on a wide spectrum of non-histone proteins, intersecting with diverse cellular processes and suggesting broader roles in metabolic signaling and protein function [77]. Large-scale lactylation histology studies confirm the presence of Kla in a large number of non-histone proteins, including NCL, YY1, and HMGB1, and these modifications regulate transcription, signal transduction, and ribosome assembly by altering protein conformation, charge distribution, and molecular interactions, thereby revealing the broad regulatory potential of lactate as a signaling molecule [78–80]. Overall, while lactylation represents an intriguing link between metabolism and epigenetic regulation, the current understanding remains preliminary. Key questions including the existence of lactyl-CoA in vivo, the physiological relevance of non-enzymatic lactylation, and the identification of specific reader proteins must be resolved before lactylation can be fully established as a stable and universal regulatory mechanism.

Regulatory enzymes of lactylation
During the modulation of lactylation dynamics, the coordinated actions of putative ‘writer’ and ‘eraser’ enzymes are proposed to contribute to the maintenance of epigenetic homeostasis and metabolic balance within the cell. The ‘writer’ enzyme is hypothesized to catalyze the transfer of lactate-derived metabolites (likely via lactoyl-CoA) to lysine residues on proteins, resulting in lactylation modifications that influence gene expression, chromatin structure, and cellular phenotype. In contrast, ‘eraser’ enzymes may remove these modifications, thereby modulating epigenetic plasticity and responding to metabolic cues. Although the identity of a bona fide lactyltransferase remains undetermined, the acetyltransferase p300 has been suggested as a candidate enzyme capable of mediating both histone (such as H3 and H4) and non-histone lactylation under certain conditions. For instance, in the fibrotic microenvironment where lactate accumulates and is taken up by macrophages and myofibroblasts, p300 has been implicated in promoting lactylation at macrophage-related loci, potentially contributing to the progression of pulmonary fibrosis [81]. Similarly, pharmacological inhibition of p300 has been reported to attenuate lactate-induced myoblast differentiation and reduce H3K9 lactylation at the Neu2 promoter, supporting a regulatory role of p300 in lactate-responsive transcriptional control [82].
Regarding ‘eraser’ enzymes, HDAC1, HDAC3, and members of the SIRT family have been identified in vitro as possessing delactylation activity [83]. Moreno-Yruela C et al. introduced the delactylases effectiveness of nicotinamide adenine dinucleotide-dependent HDACs. Researchers demonstrated that nuclear HDAC1-3, in association with SIRT (dual classified into class III HDACs), exhibited vibrant activities towards delactylases in vitro and inhibited Kla of both H3K18 and H4K5, among which HDAC3 predominates as the leading eraser in a zinc-dependent manner [83]. Nevertheless, these findings are largely based on in-vitro studies, and their in-vivo significance remains to be confirmed. To date, specific ‘reader’ proteins capable of recognizing lactyl-lysine residues have not yet been identified, and the molecular mechanisms underlying lactylation signal interpretation remain elusive. Collectively, while lactylation and delactylation appear to constitute a regulatory system analogous to other lysine acylations, our current understanding especially in living systems, remains preliminary and requires further experimental validation (Fig. 1).

Functional implications of lactylation

Functional roles of histone lactylation
Histone lactylation represents one of the earliest identified forms of lactate-dependent epigenetic regulation. Zhang et al. initially identified histone lactylation in 2019, proposing it as a novel form of epigenetic regulation that preliminarily connected lactate metabolism to transcriptional control [15]. This modification depends on lactate availability and acts as a metabolic-chromatin bridge that modulates transcriptional output and cellular fate [15]. Functionally, histone lactylation influences gene transcription primarily through changes in chromatin accessibility rather than DNA sequence [75]. Compared with acetylation, Kla presents distinct temporal dynamics and is highly responsive to metabolic stress [15]. However, its in-vivo prevalence, regulatory enzymes, and biological significance remain to be comprehensively established.
Among the identified sites, H3K18la is the best characterized, promoting the transcription of tissue-repair and anti-inflammatory genes such as Arg1 during M1-to-M2 macrophage polarization [15, 84]. Notably, elevated H3K18la has also been linked to infection resolution, where it mediates a shift from pro-inflammatory to reparative gene programs [84]. Beyond immune regulation, lactylation also participates in developmental processes. Yang et al. (2021) reported that lactate-induced histone lactylation (H3K23la) contributes to uterine endometrial remodeling and supports early embryonic development, underscoring its regulatory role in reproductive physiology [85]. Subsequent studies have extended the functional spectrum of histone lactylation beyond immune regulation to developmental and differentiation contexts, which has been observed in embryonic stem-cell differentiation, endometrial reconstruction, and osteogenic development [86–88]. More recently, Li et al. (2025) revealed that lactate dynamically regulates histone lactylation at H4K5la, H4K8la, and H4K12la during meiotic prophase I in mouse spermatogenesis. H4K8la is enriched at promoters of meiotic genes and recombination hotspots, co-localizing with SPO11, DMC1, RAD51, and cohesin components (RAD21L, REC8), suggesting that lactylation serves as a metabolic cue coordinating gene activation and recombination during germ-cell meiosis [89].
Recent evidence further indicates that H3K14la contributes to neuronal ferroptosis after intracerebral hemorrhage by upregulating PMCA2 and impairing calcium efflux, thereby aggravating neural injury [90]. In head and neck squamous cell carcinoma (HNSCC), increased histone lactylation, particularly at H3K9la, is associated with poor immunotherapy response. H3K9la enhances the expression of interleukin-11 (IL-11), which subsequently triggers immune checkpoint activation through the JAK2/STAT3 signaling pathway, ultimately impairing CD8⁺ T cell activity and facilitating tumor growth. Knockdown of IL-11 reverses T cell exhaustion and enhances immunotherapy efficacy. Clinically, H3K9la correlates with IL-11 expression and unfavorable outcomes [91]. In addition, Cai et al. (2025) identified H3K27la as a lactate-responsive histone mark that promotes trained immunity. Through fueling the TCA cycle and enhancing chromatin accessibility, lactate-dependent H3K27la upregulates cytokine expression and strengthens innate immune memory, linking metabolic flux to long-term epigenetic reprogramming in monocytes.
Beyond experimental models, clinical evidence also supports the diagnostic relevance of histone lactylation in human immune responses. In a prospective cohort study of patients with sepsis, Wang et al. (2025) demonstrated that neutrophil H4K5la and T-cell H3K56la levels are markedly elevated during acute infection and correlate with immune activation. Importantly, neutrophil H4K5la on day 1 served as an independent predictor of sepsis, and its combination with C-reactive protein (CRP) significantly improved diagnostic accuracy. Conversely, decreased lactylation on day 3, particularly reduced Pan Kla and H3K56la, was associated with unfavorable outcomes, suggesting that immune cell lactylation may serve as a dynamic biomarker for disease progression and prognosis. Histone lactylation and its various biological functions are summarized in Table 1. The table presents a comprehensive overview of the representative histone lactylation marks and their reported roles in different cellular processes.

Functional roles of non-histone lactylation
Beyond chromatin regulation, lactylation has been increasingly recognized on a broad spectrum of non-histone proteins, extending the influence of lactate from epigenetic control to post-translational signaling. These modifications alter protein conformation, stability, and intermolecular interactions, thereby impacting inflammation, metabolism, and tumor progression. One well-characterized non-histone substrate is HMGB1, a chromatin-binding protein with extracellular cytokine-like activity. Through p300/CBP-dependent lactylation, lactate promotes the nuclear-to-cytoplasmic translocation of HMGB1, which is subsequently secreted in exosomes and contributes to endothelial dysfunction and sepsis progression [80]. This finding reveals that lactate-mediated modifications can reprogram immune and inflammatory responses independently of chromatin remodeling. Further evidence highlights the metabolic sensitivity of non-histone lactylation. Nucleolin (NCL) exhibits lactylation at K102 and K116, correlating with cytoplasmic lactate levels and affecting its functions in rRNA transcription and ribosome biogenesis [92]. Likewise, YY1 lactylation at K183, mediated by p300, enhances FGF2 transcription in retinal microglia, promoting pathological angiogenesis (Fig. 2) [79]. In addition, lactate-induced lactylation stabilizes HIF-1α under normoxic conditions, facilitating its transcriptional activity on angiogenic targets (KlAA1199 axis) in prostate cancer cells and contributing to vascular remodeling [93].

Global proteomic analyses have revealed that non-histone lactylation is widespread, particularly in the cytoplasm of hepatocellular carcinoma cells, where it regulates intracellular signaling and metabolic enzyme activity [77]. Importantly, delactylase enzymes, such as HDAC1, HDAC3, and SIRT family members, have been shown to remove lactyl groups in vitro, suggesting that non-histone lactylation is dynamically reversible and may constitute a regulatory network parallel to acetylation [94]. However, the substrate specificity, compartmental localization, and physiological relevance of these delactylases in vivo remain incompletely understood, and no specific “reader” proteins have yet been identified to interpret lactylation marks.
Functionally, non-histone lactylation has been implicated in immunoregulation. In macrophages, for example, lactylation may reinforce M2-like polarization, likely complementing the Arg1-driven mechanism previously discussed [95]. More broadly, lactylation appears to promote the expression of anti-inflammatory genes and facilitate immune evasion, thereby contributing to an immunosuppressive microenvironment. These findings suggest that targeting the lactylation machinery may offer therapeutic potential. For instance, HDAC inhibitors, some of which possess delactylase activity, may reverse lactylation-associated immune suppression and restore anti-tumor immunity. Although direct preclinical evidence remains limited, this represents a promising direction for future investigation. Moreover, lactate-driven immunosuppressive signaling also extends beyond covalent modifications, such as through engagement with GPR81 and other metabolic sensors [15, 80, 96]. Taken together, lactate-induced non-histone lactylation represents a critical metabolic interface that bridges glycolytic activity with protein function, immune remodeling, and cellular signaling.
Moreover, lactate-associated metabolic signaling extends beyond covalent modification. Ippolito et al. (2020) reported that fibroblasts infiltrating the TME secrete lactate to shape lipid metabolic circuits through histone acetylation, highlighting how carbon flux and acyl-donor dynamics can converge on chromatin remodeling [97]. These findings underscore the broader role of metabolite-driven protein modifications in immune and metabolic homeostasis. Nevertheless, key questions remain regarding the enzymatic control, cell-type specificity, and in vivo relevance of lactylation, warranting deeper mechanistic and translational investigation. Non-histone lactylation and its functional roles are summarized in Table 2, which outlines the validated and candidate non-histone lactylation substrates along with their enzymatic regulation.

Lactate and immunity

Myeloid immune cells
Myeloid-derived suppressor cells (MDSCs) are crucial components of the innate immune system, with the ability to differentiate into various immune cell types, including macrophages, dendritic cells (DCs), and mast cells [98]. Emerging evidence suggests that lactate exerts metabolic effects beyond its conventional role within these immune lineages, and also plays a multifaceted regulatory role. Specifically, lactate is actively involved in immunoregulatory processes through metabolic crosstalk and cytokine-mediated signaling pathways [98, 99].
In addition to these effects, lactate also functions as a signaling molecule that activates MDSCs via the GPR81 receptor through the mTOR/HIF-1α/STAT3 axis. This lactate-induced activation of MDSCs plays a crucial role in promoting an immunosuppressive phenotype, which significantly impairs the effectiveness of anti-tumor immune responses [100]. Furthermore, metabolic reprogramming in tumor cells, marked by heightened lactate secretion, is linked to tumor progression and immune suppression in the TME. Lactate influences immune cell activity, including macrophages, DCs, and T cells, fostering an immunosuppressive milieu. Resistance to anti-PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) therapy has been associated with lactate accumulation in the TME [101, 102].
Subpopulations of macrophages (M0, M1, and M2) are capable of dynamic interconversion. The M0 phenotype can be transformed into M1 or M2 subtypes depending on external stimuli. M1 and M2 subpopulations generally exhibit opposing functions: M1 macrophages release pro-inflammatory cytokines, while M2 macrophages display an anti-inflammatory phenotype involved in tissue repair and healing [25]. The interplay between lactate and macrophages exemplifies this plasticity. For instance, lactate induces M2 macrophage activation via MCT1 signaling in muscle and metabolic reprogramming in mesenchymal stem cell (MSC) secretion, promoting tissue repair and growth [103, 104].
However, this pro-repair, anti-inflammatory outcome represents only one facet of lactate’s broad functional spectrum. Recent evidence, particularly from single-cell studies, underscores that lactate’s influence is highly context-dependent and extends beyond M2 polarization, potentially sustaining inflammatory functions. This dual role is supported by distinct mechanistic insights. Beyond its role in promoting M2 polarization, lactate can be utilized by macrophages as a metabolic fuel in glucose-deprived environments, such as tumors, to sustain their energy-demanding pro-inflammatory functions [105]. The discovery of histone lactylation further reveals lactate’s capacity to directly reshape macrophage gene expression. In LPS-activated M1 macrophages, lactate-derived lactylation initiates a unique genetic program that blurs the line between classical polarization states, driving the expression of both pro-inflammatory and homeostatic genes [15]. This model of metabolic feedback is also observed in antiviral immunity, where lactate suppresses type I interferon production by lactylating the key signaling protein MAVS, revealing an unconventional immunosuppressive function [106]. Furthermore, in the tumor microenvironment, lactate can polarize macrophages toward a pro-angiogenic phenotype characterized by vascular endothelial growth factor (VEGF) production, which facilitates tumor progression [107].
In summary, the role of lactate in macrophages cannot be oversimplified as merely “promoting M2.” It functions more like a “double-edged sword,” with its ultimate effect, whether it favors pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, being tightly regulated by factors such as concentration, duration, cell origin, and the overall tissue microenvironment [108]. Future research should explore these novel perspectives to further uncover the specific molecular switches that determine the functional shift of lactate.
As professional antigen-presenting cells, DCs exhibit exceptional efficiency and immunological potency. Most importantly, the significance of DCs is being recognized in multiple fields, an exemplary case is the application of dendritic cell vaccines [109]. Nasi A et al. proposed a novel strategy of modulating DCs vaccines immunogenicity, by means of lactate-induced PPARγ pathway modification resulting in inhibitory effects on DCs maturation [110]. Moreover, in accordance with what has been discussed above, the lactate secreted by MSCs can not only induce M2 macrophage polarization, but promote the capability of DCs polarizing CD4+T cells into Th2 cells, implicating the dynamic interaction between M2 macrophages and DCs [104].
Mast cells, unique subpopulations of myeloid lineage-derived immune cells, were once perceived as effectors in allergic responses or autoimmune diseases while gradually being reconsidered as a crucial mediator participating in complicated pathophysiological processes, which is related to monocyte-macrophage system [111]. Given the observation that lactate was enriched in the inflamed tissues, researchers believed it to be an inhibitor of inflammatory cytokines production and degranulation of mast cells, dependent on MCT1 expression [112]. Lactate also regulates mast cell activation through MRGPRX2, suppressing both early (Ca2+ mobilization, degranulation) and late (cytokine/chemokine release) phases of activation [113]. Moreover, Abebayehu D et al. showed that lactate could reduce IgE and IL-33 production in an MCT1-dependent manner, involving miR-155-5p downregulation likely via HIF-1α regulation, reinforcing lactate’s role in controlling mast cell functions in inflammation [114].
Lactate has also been shown to reduce IgE-induced Syk, Btk, and ERK phosphorylation, key signals of inflammation, and inhibit passive systemic anaphylaxis in mice. In vivo, lactate injection reduced IgE-mediated hypothermia in a murine model of anaphylaxis. Furthermore, lactate suppressed the activation of MRGPRX2/MrgprB2 receptors in both human and mouse mast cells, suggesting its potential to modulate mast cell responses during allergic diseases [112].

CD4+/CD8+/Treg T lymphocytes
T lymphocytes, encompassing both CD4⁺ helper and CD8⁺ cytotoxic subsets, are the main differentiating subpopulations of naïve T cells, which possess heterogeneous populations and follow distinct differentiation trajectories [115]. Recent studies have shown that lactate exerts differential regulatory effects on CD4+ and CD8+ T lymphocytes. Moreover, emerging evidence underscores that lactate’s role in T cell immunity is context-dependent, exhibiting both inhibitory and supportive functions.
Crucially, the expression of lactate transporters varies between T cell subsets and is influenced by the immunological context, which underpins these divergent functional outcomes. In CD4⁺ T cells, extracellular lactate not only inhibits their migratory capacity, but also contributes to their conversion to a proinflammatory Th17 phenotype, characterized by increased expression of cytokines such as IL-2 and IL-17 [116, 117]. Lactate uptake in CD4⁺ T cells can be mediated by MCT1, and notably, by the sodium-coupled monocarboxylate transporter 2 (SMCT2) in specific contexts, which in turn affects intracellular glycolytic activity [116]. Conversely, under specific conditions such as the TME, lactate robustly promotes the activation, expansion, and suppressive role of regulatory T cells (Tregs), a pivotal mechanism in the establishment of immunosuppression [118]. This effect is largely dependent on lactate uptake via MCT1, which enables Tregs to utilize extracellular lactate as an alternative fuel under glucose-deprived conditions. The lactate-driven metabolic reprogramming enhances mitochondrial oxidative phosphorylation and sustains Foxp3 expression, thereby reinforcing the immunosuppressive phenotype of Tregs. In addition, lactate-mediated histone lactylation has been implicated in stabilizing Treg lineage commitment and functional persistence, further contributing to immune tolerance within TME [118].
The effects on CD8+ T cells are equally dichotomous. While lactate impairs the motility and cytolytic function of effector CD8+ T cells, it does not inhibit glycolysis in these cells, unlike in CD4+ T cells, yet still compromises their mobility, thus blunting their cytolytic function [116]. In CD8+ T cells, MCT1 serves as the primary lactate importer, mediating these inhibitory effects [116]. Similar studies confirmed that CD8+ T cells in a lactate-rich environment exhibited reduced motility, suppressing degranulation and cytotoxin secretion by decreasing the abundance of effector CTLs at multiple steps. Owing to impaired maneuverability, CTLs are more likely to either fail to effectively engage with targeted tumor cells or have difficulty detaching from them, leading to prolonged contact, both of which hinder the effectiveness of tumor elimination.
Recent findings indicate that lactate supports the survival and persistence of CD8+ memory T cells, especially under nutrient stress. This includes conditions such as exercise or acute infection. This effect is mediated through both metabolic and epigenetic mechanisms. Due to their relatively low glycolytic activity, memory CD8+ T cells rely more heavily on exogenous lactate uptake via MCT1, which sustains intracellular lactate levels and promotes histone H3K9 lactylation (H3K9la). This modification is enriched at promoter regions of genes involved in OXPHOS, fatty acid oxidation, and memory-associated factors, contributing to the long-term functional maintenance of memory T cells. Through this mechanism, lactate enhances mitochondrial function and metabolic reprogramming, which are essential for the endurance and longevity of memory CD8+ T cells. Moreover, H3K9la-mediated transcriptional activation supports effector potential retention and adaptation to metabolic stress. These findings collectively suggest that lactate acts not only as an alternative energy substrate but also as a key epigenetic modulator, enabling CD8+ memory T cells to persist and function effectively over extended periods [119].
Therefore, reduced cytotoxic ability associated with limited killing scope is likely to reinforce the conceptual assumption that lactate exhibits remarkable potential to coordinate the spatial distribution and modulate the biological functions of CD8+ T cells [120](Fig. 3). Collectively, lactate acts as a metabolic checkpoint that can simultaneously suppress effector T cell functions while fostering immunosuppressive Tregs and, paradoxically, supporting the foundation of long-term immunity via memory CD8⁺ T cells, highlighting a sophisticated and context-dependent immunomodulatory profile.

Lactate and disease

Immunity-related diseases
Immune responses intersect with a diverse range of disease occurrences. Apart from being involved in metabolic activities, lactate has exhibited remarkable potential in immune regulation [99]. Targeting specialized immune cell populations with high heterogeneity, lactate interacts with them in a dynamic manner. Inflammatory diseases are often accompanied by immune system disorders when lactate metabolism is disrupted. Therefore, to deepen the understanding of lactate’s diverse immunoregulatory roles across different immune cell populations involved in immune-related diseases, we aim to provide a detailed explanation in this section.

Rheumatoid arthritis
For the past few decades, the parallel relationship between lactate and rheumatoid arthritis (RA) has been recognized owing to lactate enrichment in synovial cells, endowing it with the trait of being a reliable indicator for differentiating RA [17]. This phenomenon suggests enhanced glycolytic metabolic tendency in synovial cells. Peng et al. proposed aerobic glycolysis-dominant metabolic pathway with responsive LDHA concentration increase in activated T cells, releasing IFN-γ and maintaining histone acetylation to promote effector T cell functions [121]. However, constrained CD4+/CD8+ T cells motility were also observed for different reasons when extracellular lactate concentration increased, mediated by SMCT2 on CD4⁺ T cells and MCT1 on CD8⁺ T cells, and was retrospectively shown to correlate with T cell function in RA synovia [116].
Consequently, the impaired migration ability caused CD4+/CD8+ T cells’ prolonged retention in synovial fluids, where lactate could promote CD4+ T cells to transform into Th17 subsets producing abundant IL-17, and to reduce the cytolytic capacity in CD8+ T cells, possibly owing to autoantibody and ectopic lymphoid structures [122]. Additionally, the decreased pH running parallel to the RA activity is facilitated by MCT4, which exports lactate from synovial fibroblasts (RASFs) [122]. Compelling preclinical evidence positions MCT4 as a key therapeutic target. In RA patients, MCT4 is upregulated in RASFs, directly contributing to synovial fluid acidification. Crucially, in a mouse model of collagen-induced arthritis, targeted silencing of MCT4 within the articular synovium significantly attenuated disease severity by inducing apoptosis in RASFs, offering direct proof-of-concept for this approach [122].
Furthermore, considering the specific transporter SMCT2, highly expressed on CD4+ T cells, this biological characteristic provides an essential influx route for lactate ingestion. Once intracellular lactate is sufficient to induce CD4+ T cell phenotype transformation, RORγT-dependent IL-17 expression via activation of the PKM2-STAT3 axis would be initiated, confirming lactate as a critical mediator in inflammation-related diseases, including RA. Moreover, in correspondence with what was delineated above, the extracellular lactate accumulation would lead to localized CD4+ T cell retention in inflamed lesions due to inhibited motility, as a consequence of glycolytic activity inhibition [123]. Haas R et al. further elaborated on this phenomenon: CD4+ T cell movement limitation was found to involve the CXCR3/CXCL10 axis, while CD8+ T cell motility does not apply to this regulatory mechanism, presumably due to the loss of cytolytic effectiveness [116].
Therefore, both T cells and lactate are closely correlated with chronic inflammation, revealing the detailed clues comprising the delicate lactate interaction with cellular metabolism and behavioral adjustments (Fig. 4).

Ulcerative colitis
Ulcerative colitis (UC), a chronic bowel disease with immune disorders involving the colon and rectum, has contributing pathogenic factors characterized by individual heterogeneity, such as environmental factors, genetic susceptibility, and immune imbalances. Since the efficacy of TNF-α treatment was demonstrated in clinical trials in the 2000 s, the UC management strategy has evolved into a paradigm shift towards healing at the histological level, aiming to improve patient diagnosis and quality of life as much as possible [124].
Admittedly, gut microbiome disorder is one of the underlying causes of UC. Dietary management based on anti-inflammatory principles has also recently been utilized as a recommended therapy to reduce immunosuppressive agent-induced adverse effects [125]. Thus, considering the high abundance of lactate production mostly derived from specific gut bacterial communities such as bifidobacteria and lactobacilli, it is worthwhile to analyze the complex and context-dependent roles of lactate during UC-related gut microbiome disorders [126]. Mechanistically, studies in mouse colitis models by Ranganathan et al. identified GPR81 on colonic dendritic cells and macrophages as a key suppressor of inflammation, promoting Tregs and limiting Th1/Th17 responses. These findings suggest GPR81 is a compelling preclinical target. However, its clinical translatability requires evaluation, particularly given the complex, context-dependent role of lactate in human UC, where its accumulation can also be pathogenic [127]. In conjunction with this finding, intrarectal lactate administration induced symptom relief in a murine colitis model. The possible explanations include the potential to reduce serum IL-6 levels, disrupting metabolic activities correlated with proinflammatory cytokine release [128]. Of note, on the basis of epigenetic modification, another study contextualized the significance of lactate-promoting effects on histone H3K18 lactylation in association with histone H3K9 acetylation in UC management, by increasing MCT-induced macrophage lactate uptake, suppressing NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, and reducing macrophage pyroptosis induced by caspase-1 expression [129].
However, the beneficial, anti-inflammatory role of lactate contrasts with observations in human UC patients. Metagenomic and metabolomic analyses of human gut microbiota have revealed that microbial dysbiosis can lead to excessive lactate accumulation in the colonic lumen. This overabundance of lactate is associated with a worsened disease state, potentially by creating a pro-inflammatory microenvironment, disrupting the balance of short-chain fatty acid production, and directly impairing epithelial barrier function [130]. Therefore, as evidenced by current observations, lactate metabolism may possess a dual immunomodulatory propensity that is tightly regulated by the gut microbial ecology and metabolic context. The impact of lactate, whether beneficial or harmful, depends on various factors, including its concentration, origin, and the overall condition of the host’s microbiome and immune system.

Allergic diseases
Given the observation that lactate plasma concentration in patients with asthma increases in conjunction with disease severity, the relationship between lactate and asthma has drawn widespread attention. Irvin C et al. found that significant enrichment of Th2 and Th17 lymphocyte subsets identified within bronchoalveolar lavage samples obtained from individuals diagnosed with asthma could trigger IL-4 overproduction and subsequently augment the capability of inducing glucocorticoid resistance in vitro [131]. Given that lactate could reinforce this through delicate immunomodulatory propensity, it could help explain its corresponding roles in allergy.
However, another immune cell subpopulation closely associated with allergic reactions is mast cells, as mentioned above. When stimulated by lactate administration, mast cells tend to reduce the production of both IgE and IL-33 cytokines [114]. This finding indicates the therapeutic potential of lactate in alleviating allergic responses through inhibiting the release of endogenous sensitizing substances.
To summarize, immunometabolic activities are of great significance in allergic diseases. Lactate possesses the propensity to alter allergy-associated immune cell phenotypes from intrinsic perspectives, helping to maintain or disrupt immune balance.

Cardiovascular disease
As a crucial energy substrate, lactate utilization covers a large proportion of the energy in cardiomyocytes. The clinical relevance of lactate in myocardial infarction (MI) is firmly established in human studies, which consistently show that elevated blood lactate levels serve as a powerful prognostic indicator, being strongly associated with higher mortality and poorer outcomes in patients with acute MI [132]. However, the dual role of lactate is evident as it also contributes to the progression of myocardial fibrosis and worsens cardiac dysfunction by facilitating endothelial-mesenchymal transition (EndoMT) following MI [133].
The functional significance of lactylation at the α-MHC K1897 site in regulating cardiac contractility was first characterized in mouse models. Proteomic analysis revealed decreased K1897 lactylation in failing hearts. Mechanistically, mice engineered with an α-MHC K1897R substitution mutation exhibited impaired α-MHC-Titin interaction and exacerbated cardiac dysfunction. Importantly, increasing intracellular lactate levels, either by lactate administration or inhibition of the lactate exporter MCT4, alleviated cardiac dysfunction in these models, suggesting a potential therapeutic mechanism mediated by K1897 lactylation [18].
While lactylation is an evolutionarily conserved modification, the existence and functional role of this specific α-MHC K1897 lactylation event in human cardiomyocytes remain unvalidated and represent a critical area for future research. Beyond its role in modifying structural proteins like α-MHC, lactylation also functions as an epigenetic mark. For instance, it modifies key transcription factors and histones, such as H3K27, which is closely correlated with gene expression levels in end-stage heart failure [134]. This broader regulatory role enables lactylation to coordinate the expression of genes involved in myocardial repair following injury [18, 135].
Based on this assumption, and considering that lactate depletion may aggravate myocardial dysfunction, research has explored whether MCT4 inhibitors could reverse ventricular remodeling at early onset. Coinciding with this assumption, Cluntun et al. found that inhibiting lactate export could also ameliorate hypertrophic phenotype transformation mediated by the pyruvate-lactate metabolic shuttle axis. Given the myocardial propensity to consume exogenous Cori cycle-produced lactate, lactate consumption in cardiomyocytes is normally balanced with the rate of glycolytic pyruvate-derived lactate production, commonly known as the pyruvate-lactate axis. The circulatory abundance fluctuation between lactate and pyruvate is a decisive factor contributing to cardiomyocyte maintenance. However, this axis balance is disrupted when cardiomyocytes prefer pyruvate-derived lactate production, accompanied by a concomitant decrease in lactate consumption at the onset of heart failure [136]. This study identified both the MPC and MCT4 as central nodes in this metabolic intersection. MCT4 blockade (VB124) administration was then tested for its capacity to mitigate hypertrophy in cultured mouse cardiomyocytes [137]. In murine models of type 2 diabetes, MCT4 inhibition alleviated myocardial oxidative stress and pathological injury. It is crucial to note, however, that recent studies highlight significant systemic side effects of MCT4 inhibition due to its broad tissue expression, which may limit its clinical translational potential and necessitate the development of tissue-specific delivery strategies [138].
However, it is important to note that recent studies on MCT4 inhibition have revealed significant systemic side effects that may limit its clinical translational potential. Specifically, MCT4 is widely expressed in various normal tissues, where it plays a crucial role in lactate efflux. Its systemic inhibition could lead to lactate acidosis, metabolic disturbances, and impaired immune function, among other adverse events [68]. Therefore, while MCT4 plays an important role in regulating myocardial metabolism, developing tissue-specific targeting methods or seeking combination therapies may be key strategies to overcome these side effects in the future.
Paradoxically, the clinical relevance of modulating lactate is supported by human studies. For instance, administration of sodium lactate was shown to significantly enhance cardiac performance in patients with acute heart failure, suggesting that the timing and context of lactate modulation are critical and that boosting lactate levels can be beneficial in certain clinical scenarios [139]. This finding contrasts with MCT4 inhibition strategies and introduces another important perspective, regulation through lactate-specific influx transporters, such as MCT1.
Another revealing perspective is based on the lactate-specific transporter MCT1. Given the increased reliance on lactate for oxidation in impaired cardiomyocytes, these specialized transporters have inevitably received much emphasis. MCT1, as the lactate influx transporter in the sarcolemma, was found to be extensively upregulated in rats with congestive heart failure. Another contributing factor was the formation of a novel cell-intrinsic MCT1 pool in conjunction with specific sarcoplasmic membranes oriented toward the T-tubules [140] (Fig. 5).
Therefore, lactate plays a dual role in cardiovascular disease, serving both as a critical energy substrate for cardiomyocytes and as a modulator of pathological processes such as fibrosis and cardiac dysfunction through lactylation and transporter-mediated mechanisms.

Obesity
The role of lactate in obesity and insulin resistance is complex and exhibits apparent contradictions, which can be reconciled by considering dose, temporal context (chronic elevation vs. acute supplementation), and specific tissue environments. Unequivocally, recent reports have indicated an alternative metabolic pathway for lactate, in association with lipid anabolism. Lactate enrichment pertains to fatty acid synthesis by serving as a supplementary source of acetyl-CoA, concurrently activating related carboxylases responsible for promoting fatty acid production during shuttle and exchange processes. Seemingly, lactate has been explored as a substrate for lipid storage, and in some cases, it can also promote fatty acid synthesis in rat muscles through glyceroneogenesis-derived glycerol [141]. Contrary to this belief, under an excessive abundance of fatty acids, lactate could responsively exhibit a stimulating effect on fatty acid oxidation through the TCA cycle [19]. The blood tests also demonstrated the negative association between lactate and lipid-oxidation, suggesting that lactate may possibly suppress fatty acid oxidation [142]. A prospective case-control study involving 24 severely obese patients was accompanied by hyperinsulinemia secondary to hyperlactatemia [143].
Nevertheless, the interplay between lactate and insulin resistance in obesity remains multifaceted and often contradictory, as further discussed below. Admittedly, the rise of lactate levels in adipose tissues of obese individuals has long been understood. In the context of chronic hyperlactatemia, lactate is viewed as both a byproduct and a contributor to metabolic dysfunction and systemic inflammation [144].
To reveal lactate’s role in this dynamic process, researchers found that manipulating MCT1-mediated lactate transport led to notable effects. Specifically, MCT1 is abundantly expressed in adipose cells, and selective blockade agents have been shown to cause cell-intrinsic lactate retention, thereby stimulating adipocyte apoptosis, promoting pro-inflammatory cytokine release, and exacerbating insulin resistance in both adipose and surrounding tissues [144]. However, the detailed mechanism responsible for this sequential phenomenon remains vague. Transcriptome analysis revealed a strong association between MCT1 deletion and alterations in inflammation and apoptosis within adipose cells. The inflammatory response appears to be secondary, triggered after lactate-induced apoptosis in adipocytes. These activities could be aggravated by MCT1 inhibition, accompanied by cytokine production, infiltration of inflammatory adipose tissue macrophages (ATMs), and the emergence of insulin insensitivity in nearby tissues [144]. In line with this finding, researchers also discovered that both ATMs and pro-inflammatory cytokines were diminished in the lack of lactate. Mouse models with selective deletion of LDHA exhibited improved glucose tolerance and insulin sensitivity. The specific mechanism may involve adipocyte-derived lactate enhancing ATM polarization into inflammatory subsets by binding competitively to the PHD2 catalytic domain in macrophages, stabilizing HIF-1α expression, and augmenting IL-1β production. These effects were alleviated when lactate was depleted, suggesting that endogenous lactate may enhance inflammation in obesity-related insulin resistance [145].
In stark contrast, exogenous lactate administration at moderate doses in experimental settings reveals a protective, pharmacodynamic potential. This paradigm demonstrates that when introduced as a signal to a stressed system, lactate can activate beneficial pathways. Paradoxically, exogenous lactate supplementation at moderate doses demonstrates protective effects. For instance, when Cai H et al. administered moderate doses of L-lactate (800 mg/kg/day) to mice exposed to a high-fat dietary regimen, they observed suppression of M1 polarization in ATMs. The 12-week lactate administration showed potential in reducing body weight gain and improving insulin sensitivity, indicating therapeutic potential in type II diabetes associated with obesity [146]. Moreover, other studies have reported lactate as a possible dietary supplement acting via the GPR81 receptor. Oral lactate administration was shown to induce GPR81 expression, promoting adipose browning as an anti-obesity mechanism. A possible explanation involves lactate activating the p38-UCP1 axis, supporting the hypothesis that lactate-activated GPR81 may cooperate with β3-adrenergic receptors to enhance thermogenesis [147]. This concentration-dependent effect is epitomized in energy metabolism during exercise, where a shift from white adipose tissue to intramuscular triglycerides as the primary fatty acid source occurs as blood lactate rises from 2 mM to 5 mM, demonstrating lactate’s role as a metabolic rheostat in real-time [148].
In conclusion, the dualistic role of lactate in obesity is not only dependent on its concentration and exposure duration but is also fundamentally governed by the distinct metabolic and signaling pathways it engages in different tissues. As comprehensively reviewed, lactate exhibits “tissue specificity”: in white adipose tissue, it can suppress lipolysis via the GPR81 receptor at high concentrations, yet promote lipolysis and browning via β3-adrenergic receptor and mitochondrial pathways at lower concentrations or under specific conditions such as exercise [149, 150]. Concurrently, in skeletal muscle, lactate can inhibit fat breakdown and promote triglyceride accumulation through the GPR81-cAMP-PKA axis, while simultaneously enhancing mitochondrial biogenesis and oxidative function through metabolic pathways [9, 151]. This intricate, context-dependent network of actions positions lactate not merely as a passive biomarker of metabolic stress, but as an active rheostat that fine-tunes energy substrate utilization across tissues. Future therapeutic strategies must therefore move beyond a simplistic view of lactate, and instead target its specific signaling hubs to harness its beneficial effects while mitigating its pathological contributions (Fig. 6).

Sepsis
Fairly speaking, lactate serves as a critical but non-specific biomarker in sepsis, reflecting the body’s metabolic stress rather than solely hypoxic conditions. Current sepsis guidelines emphasize that while lactate is a strong prognostic indicator for mortality and the need for resuscitation, its elevation has multiple causes beyond global hypoperfusion [152].
Traditionally, lactate is viewed as a byproduct of anaerobic glycolysis during hypoxia, and hyperlactatemia in sepsis often mirrors circulatory hypoperfusion and the associated decreased pH levels [2]. However, a paradigm shift recognizes that a significant portion of lactate production in sepsis, particularly in hyperdynamic septic shock, stems from adrenergic stimulation-induced aerobic glycolysis (the “Staub-Effect”) in well-oxygenated tissues. This explains the paradoxical observation of significant hyperlactatemia in patients without overt signs of shock, underscoring the complex relationship between lactate and sepsis [152–154]. Therefore, lactate levels, though vital for risk stratification, must be interpreted as a nonspecific marker of metabolic stress within a broader clinical context.
Undeniably, excessive glycolysis exerts significant influences on immune metabolism in severe infection. Transient adaptations to glycolysis can sometimes facilitate immune cell subtype transformations, given their characteristics of adopting metabolic configurations for better energy conservation and rearrangements [155]. The persistent elevation of hyperlactatemia symbolizes the interactive trajectory with inflammation-related cytokines and immune cells. Lipopolysaccharide (LPS)-induced inflammatory responses, as the most representative septic pathway, initiate a premise for immune cell mobilization and are a potent driver of this metabolic reprogramming.
Speaking broadly, monocyte-macrophage systems and mast cells are significant immune subpopulations at septic onset. For instance, considering the crucial functions of mast cells in sepsis, researchers discovered that lactate suppressed the production of LPS-induced cytokines and NF-κB transcriptional activities dependent on MCT1, based on disrupting the constant energy metabolic circulation [156]. Focusing on energy metabolism, sustained ATP production is the decisive force to maintain the intracellular physiological processes. What could be presumed on lactate was its capability to disrupt normal metabolism, thus impairing the corresponding immunity in the sepsis process [157]. More precisely, the activation of LPS is usually accompanied by reinforced glycolysis, which could ensure adequate energy availability for the smooth operation of NF-κB transcriptional activities and cytokine releases; this dynamic process could be suppressed by exogenous lactate. This lactate propensity implied the vicious circle of sepsis, where patients at their terminal stages always exhibited refractory and critical immunosuppressive effects [156, 158]. A similar suppressive phenomenon was observed in bone marrow-derived macrophages (BMDMs) in multiple pathways. Dependent on the GPR81 receptor, researchers found that lactate inhibits activation of the inflammatory cascade via TLR4 signaling, including the NLRP3 inflammasome and NF-κB signaling. Furthermore, the synthesis of IL-1β was subsequently diminished [159].
Beyond that, based on previous assumptions, lactate was surprisingly discovered to exhibit inhibitory effects on wild GPR81(-) macrophage cell lines, which included abrogating LPS-induced IL-6 expression depending on concentration. The non-specificity of this process implied that lactate could exert remarkable influences via other alternative pathways, such as MCT1-dependency, which was assessed to be expressed in macrophages [160]. Apart from this, neutrophils localized in the bone marrow possessed the propensity to produce lactate during the early stages of infectious disease induced by LPS, on the basis of increasing glycolysis, ROS burst primarily derived from NADPH oxidase (NOX) activity, and HIF-1α. The overproduction of lactate would thus be secreted into the circulation through MCT4 and preferentially bind to GPR81 on endothelial cells, to reduce endothelial VE-Cadherin expression and increase vascular permeability through different signaling. This whole dynamic process promoted neutrophil mobilization to a large extent [161]. This host of evidence provides a reasonable conjecture where immune compromises might occur in a lactate-rich circumstance, in conjunction with a group of innate immune cells escalating this route, which are believed to be the first guard to defend the bacterial invasion. For the time being, the studies investigating lactate effects on adaptive immunity in septic pathogenesis are comparatively limited, so more detailed mechanisms require further verification.
Additionally, from the post-transcriptional modification perspective, researchers extracted blood samples from clinical subjects and explored the ubiquitous lactylation in global protein modifications in peripheral blood mononuclear cells both in healthy and shock patients, among which the major subpopulation is H3K18 lactylation. H3K18 lactylation was significantly correlated with the infectious inflammatory cytokines, concurrently prompting ARG1 overexpression in response to inflammation. Therefore, the general H3K18 lactylation status portrayed the landscape associated with the severity and prognosis [84] (Figs. 2 and 7).

Injury

Wound healing
Wound healing is a multifaceted process marked by cellular variation, structural complexity, and functional malleability, during which age-related factors and diabetes are recognized as key contributors to the development of persistent wounds [162]. Wound healing typically progresses through three overlapping phases, including inflammation, proliferation, and tissue remodeling [163]. In general, the post-injury process requires coagulation initiated by interactions between endothelial cells and platelets, whose released mediators trigger an inflammatory response that recruits neutrophils and macrophages. These immune cells release proinflammatory cytokines and growth factors that stimulate stromal cells to mature into myofibroblasts, which promote wound contraction and deposition of extracellular matrix components, enhance epithelial cell proliferation, and induce neovascularization. Eventually, macrophages and extracellular protein-hydrolyzing enzymes remove clots and tissue debris to complete the repair process [164]. Due to the excessive secretion of cytokines during this process, metabolic activities increase rapidly, leading to a hypoxic microenvironment. In this context, lactate becomes essential for a central energy source required to fulfill the metabolic demands of wound healing.
Angiogenesis is a key step in wound healing, as it supplies nutrients essential for cellular proliferation and tissue repair [165]. Porporato et al. reported that lactate can promote angiogenesis and reperfusion in ischemic wounds in mice, indicating that lactate induces healing angiogenesis [166]. Supporting this, elevated levels of VEGF have been associated with enhanced angiogenesis [167]. Given its origin in glycolytic processes, many studies have shown a dynamic link between lactate metabolism and HIF-1α: under low oxygen conditions, HIF-1α attaches to the VEGF promoter, activating its gene expression [168]. Furthermore, HIF-1α upregulation can indirectly enhance VCAM1 expression by inducing C1q binding protein (C1QBP) overexpression and activating the NF-κB signaling pathway [169]. Additionally, lactate has been found to stimulate circulating vasculogenic stem cells within subcutaneous matrix tissue via a mechanism dependent on thioredoxin 1 (Trx1) and HIF-1, forming a positive feedback loop [170].
In addition to promoting angiogenesis, lactate has also been shown to stimulate collagen production in fibroblasts, highlighting the critical role of fibroblasts in extracellular matrix synthesis during wound healing [171]. This suggests that regulating fibroblast metabolism may offer a theoretical basis for enhancing tissue regeneration. Weng et al. demonstrated that platelet-rich plasma (PRP), widely used in regenerative medicine, can stimulate glycolytic enzyme activity in fibroblasts to accelerate wound repair [172]. Moreover, lactate pretreatment was found to shift fibroblast metabolism toward glycolysis, partly through ROS-mediated HIF-1α stabilization.
Beyond fibroblasts, macrophages play a crucial role in post-injury inflammation. Lactate has been demonstrated to trigger macrophage polarization as well as promote tissue regeneration [103]. In later stages of repair, M1 macrophages may be reprogrammed to support the transcriptional activation of genes such as ARG1 [15]. Lactate has also been reported to promote macrophage polarization toward the M2 phenotype, linked to VEGF and ARG1 secretion [107]. These results suggest that lactate facilitates macrophage reprogramming toward a suppressive and tissue-repairing phenotype in response to injury.
From an epigenetic perspective, lactate acts as a “lactate clock” in late-phase M1 macrophages. This transition involves the B cell adaptor for PI3K (BCAP), which, via its N-terminal TIR domain, mediates signal transduction from TLRs to the PI3K-AKT pathway, promoting aerobic glycolysis and lactate production. Loss of BCAP impairs this metabolic shift, resulting in reduced histone Kla and diminished expression of reparative genes, accompanied by prolonged inflammation due to reactivation of FOXO1 and GSK3β. In BCAP-deficient mice, these defects could be rescued by exogenous lactate, confirming that histone Kla and reparative programs can be restored through lactate supplementation, with increased Arg1 and Klf4 expression serving as key markers of this transition [173]. Thus, lactate appears to act as a driving force for macrophage immunomodulation. An imbalance in cellular immune status influenced by lactate may affect the severity of inflammatory diseases, providing new insight into potential therapeutic approaches for chronic inflammatory wounds [174] (Fig. 8).

Anti-ROS
Reactive Oxygen Species (ROS), a key hallmark of neurodegeneration, are dependent on mitochondria for a vast majority of production, and aging mitochondria can produce substantial quantities of ROS due to dysfunction of the respiratory chain, which has been witnessed particularly in Alzheimer’s disease (AD) and Parkinson’s disease (PD) [175, 176]. AD is characterized by amyloid beta plaques with significantly increased lactate levels owing to glucose hypometabolic activities [177]. Surprisingly, the production of lactate is presumably inducing a mild release of ROS inside the mitochondria while concurrently triggering defensive mechanisms responsible for maintaining pro-survival pathways, including PI3K-AKT pathway activation and Endoplasmic Reticulum (ER) protein processing. This finding sheds light on the lactate clinical utility to treat aging-related disorders as a response-activating agent [178]. However, the lactate-induced response mechanism based on a mild ROS burst seems to be restricted in scope. Researchers have also observed this phenomenon in Schwann cells. In Schwann cells, Rheb gene knockdown was utilized to specifically inhibit PDH activity, which shifted the metabolic pattern towards a lactate-predominant oxidized route, thereby transporting increased lactate into peripheral axons. Parallel to the above findings, a slight lactate increase could fuel ATP production in the mitochondria and trigger ROS-dependent pro-survival signaling. However, prolonged exposure to ROS could exacerbate axon damage, reflecting the complexity of lactate metabolism in neuronal support [179]. In pulmonary fibrosis, lactate accumulation has already been observed with the tendency to promote disease progression. Under hypoxic conditions, lactate could enter fibrogenic mesenchymal progenitor cells through the GPR81 receptor to enhance their self-renewal, intensified by HIF-1α augmenting GPR81 expression [180]. In light of this assumption, Sun et al. continued exploring the corresponding mechanism. They found that lactate levels increased concurrently with rising ROS levels, secondary to lactate-induced alterations in mitochondrial morphology and function through DRP1 and ERK modulation [181].

Ischemia-reperfusion injury
Lactate has long been widely recognized as being involved in metabolic remodeling within the central nervous system. Across varied intrinsic energy absorption among cell types, aberrant metabolism has been shown to predispose to the pathophysiological progression of neuronal disorders [177]. Admittedly, lactate has been found to participate in various energy activities typical of glycolytic metabolism, despite excessive oxygen consumption, due to the heterogeneity of neurocytes with distinct metabolic features within the central nervous system, such as astrocytes [182]. Magistretti PJ et al. proposed a model in which lactate is transferred as a regulatory molecule rather than simply being a metabolic end-product. The lactate transported from astrocytes into neurons plays a crucial role in activating signaling cascades via MCT2 and HCAR1 (GPR81) receptors, involving plasticity-associated genes [183, 184]. Therefore, this intricate trajectory contextualizes astrocyte-neuron interactions, wherein accumulated extracellular lactate can serve as an energy source for neurons. Moreover, Suzuki A et al. proposed that MCT1/4 blockers on astrocytes could potentially increase the incidence of amnesia, thereby impairing LTP functions mediated by lactate consumption, implying the role of lactate in synaptic plasticity [47]. Furthermore, conclusive evidence was demonstrated by the observation that lactate in neurons has the potential to stimulate the expression of synaptic plasticity-associated genes such as Arc in anN-methyl-D-aspartate (NMDA) receptor-dependent manner. Lactate-induced NMDA receptor activation thus triggers calcium influx into the neuronal cytoplasm. The calcium influx then initiated a signaling cascade leading to ERK1/2 activation, which belongs to one of the MAPK subfamilies, thereby promoting gene expression associated with synaptic remodeling [33]. Moreover, increased NADH levels resulting from astrocyte-derived lactate utilization in gluconeogenesis also act as a driving force to positively stimulate NMDA receptor activity. According to Bajaffer A et al., other upregulated genes significantly related to synaptic plasticity include EGR1 and BDNF [185].
It is worthwhile to explore more specific mechanisms involved in lactate-mediated signaling and physiological maintenance. More specifically, HCAR1 (GPR81) is located at the interface between pial fibroblast-like cells and pericyte-like cells, promoting cerebral vascular endothelial growth and angiogenesis in a VEGFA-dependent manner, independently of MCTs and as an alternative pathway induced by intense exercise [186]. Consequently, some researchers have suggested promising roles for lactate in exerting protective effects, including promoting cell survival during reperfusion injury, with evidence supporting its potential to alleviate such damage. Rather than merely serving as a metabolic end-product, lactate can play a pivotal role in preventing ischemia-reperfusion injury by acting as an efficient energy source. This phenomenon is demonstrated by observations showing that lactate-induced ischemic preconditioning exerts neuroprotective effects on human model cells in vitro [187]. This finding supports the potential clinical utility of lactate in ischemic stroke. However, it is crucial to add nuance to this perspective. The beneficial role of lactate as a metabolic fuel, primarily observed in controlled experimental models, stands in contrast to clinical data from stroke patients. Clinical studies consistently associate elevated systemic lactate levels with poor prognosis. For instance, elevated lactate concentrations upon ICU admission are independently linked to higher mortality in ischemic stroke, reflecting its dual role as both a metabolic substrate and a prognostic biomarker of disease severity [188]. Thus, while lactate may support neuronal survival in controlled models, its systemic accumulation in clinical contexts often signals worse outcomes. Furthermore, a recent retrospective analysis identified the Lactate Dehydrogenase to Albumin Ratio (LAR) as an independent predictor of 3-month post-thrombolysis outcomes in ischemic stroke patients, supporting the prognostic relevance of lactate-related biomarkers in cerebrovascular events [189]. This dichotomy underscores that while locally administered lactate may be neuroprotective, elevated systemic lactate serves as a robust biomarker of global metabolic derangement and disease severity, heralding a worse clinical outcome.
Additionally, bedside microdialysis monitoring in patients with subarachnoid hemorrhage revealed that dynamic elevations of extracellular lactate and glycerol closely correlate with delayed cerebral ischemia, highlighting lactate’s utility as a sensitive indicator of acute metabolic distress in neurological injury [190]. As is well known, after encountering blood and nutrients obstructions for a time limit, normal cells will sustain irreversible damage that exacerbates cellular impairment even when reacquiring blood reperfusion, including uncontrollable pro-inflammatory cytokine storms, ROS activation, and lipid peroxidation [191]. The extent of organ damage depends on the reliability degree of absorbing oxygen from the red blood cells, so the specific cells surrounded with rapid circulatory blood, whose tissues belong to the brain or heart, are the most influenced organs by the ischemia reperfusion damage and the focus of research topic.
Beyond metabolic dysfunction, structural compromise of the neurovascular unit further contributes to ischemic injury. The basal lamina of capillaries, a structural barrier closely associated with astrocytic endfeet, also plays a key role in maintaining blood-brain interface integrity during ischemia-reperfusion [192]. Disruption of this anatomical interface impairs not only barrier integrity but also glial-neuronal metabolic coupling. Such coupling is exemplified by the ANLS hypothesis, where astrocyte-secreted lactate acts as an energy supplement for neurons during nutrient deprivation (See Fig. 9 for schematic overview). Generally, astrocyte-derived lactate is mainly released through monocarboxylate transporters; however, emerging evidence indicates that alternative release pathways may also exist [193]. For instance, recent studies in mouse models have revealed that astrocytes maintain an intracellular lactate reservoir that can be rapidly mobilized in response to neuronal cues such as elevated extracellular K+ or membrane depolarization. Specifically, a putative lactate-permeable ion channel, activated by astrocytic depolarization and exhibiting approximately 37 pS conductance, has been identified in vitro; this channel appears to be positively modulated by intracellular lactate levels, forming a possible feedback loop for rapid lactate efflux [13]. Moreover, connexin hemichannels, which are traditionally associated with ATP and metabolite release, have been implicated in lactate transport during hypoxia or intense synaptic activity. Although pannexin channels are primarily known for mediating ATP release, some experimental evidence suggests they may also participate in lactate flux under specific non-homeostatic conditions, though this remains speculative and requires further validation [14]. These findings from animal models suggest that astrocytic lactate release may involve multiple pathways beyond monocarboxylate transporters, allowing adaptive responses to neuronal energy demands and pathological stress.
Crucially, the functional significance of this lactate shuttle has been strongly supported by interventional studies. Specifically, downregulation of the neuronal lactate transporter MCT2 or the astroglial lactate transporter MCT4 in the rat barrel cortex abolished the lactate rise in response to sensory stimulation. Under the same conditions, the hemodynamic response measured by blood oxygen level-dependent (BOLD) functional MRI, a primary technique for visualizing brain activity by detecting local changes in blood oxygenation and flow that correlate with neural activation, was completely prevented in all MCT2-downregulated rats. Intriguingly, approximately half of the MCT4-downregulated animals also lost their BOLD response, and this deficit could be rescued by peripheral lactate infusion, a rescue not possible in MCT2-downregulated rats. When assessed behaviorally, MCT2-downregulated animals were impaired in a textured object recognition task, while a similar proportion of MCT4-downregulated animals (about half) showed an identical deficit, mirroring the bifurcation observed in the neurovascular responses. These data collectively demonstrate that ANLS is indispensable for both the neurometabolic and neurovascular coupling processes that underpin functional brain imaging signals and is necessary to sustain behavior driven by cortical activation [194]. It is important to note that beyond its role as an energy substrate, lactate also functions as a signaling neuromodulator. Activation of the lactate receptor HCAR1 has been consistently shown to decrease the activity and excitability of cortical neurons via both pre and postsynaptic mechanisms. This modulatory role, which is distinct from its metabolic function, adds another layer of complexity to the interpretation of neurovascular coupling and may contribute to the BOLD signal [195]. Therefore, the observed effects of lactate shuttling on brain activation and behavior likely involve the integrated contribution of both its energy-delivering and its signal-transducing functions.
Additionally, within the peripheral nervous system, Schwann cells play a crucial role in this process, undergoing metabolic reprogramming via upregulated glycolysis to protect injured axons [196]. Furthermore, the augmented mammalian target of rapamycin complex 1 (mTORC1) pathway mediates the glycolytic shift and sustained energy support, in conjunction with downstream signals of both HIF-1α and c-Myc, thus responsively protecting injured axons [197]. Most importantly, post-injury axons undergo a dramatic upregulation of MCTs, suggesting enhanced lactate influx to meet increased energy demands as a protective mechanism [197]. However, other studies have revealed that lactate-induced neuroprotective effects may only occur in the presence of specific anesthetics, due to its potential to shift the preferential metabolic route when ATP stores are depleted [198]. Similar studies have also reported lactate’s protective effects in conjunction with isoflurane anesthesia administration [199]. Thus, whether lactate can be used as a protective agent in ischemia-reperfusion remains to be conclusively determined.
Additionally, lactate has been investigated as a potential post-treatment for myocardial cells after infarction [200]. A recent study identified a significant intestinal metabolite, indole-3-lactate, as a protective agent that alleviates intestinal ischemia-reperfusion in mouse models by regulating YAP and Nrf2 [201]. More specifically, compared with earlier assumptions, researchers focusing on lactate-promoted protective effects after organ ischemia-reperfusion are scarce. Possible reasons may include the difficulty in distinguishing the effects of endogenous versus exogenous lactate, as well as challenges in translating findings into broad clinical applications.

Lactate and tumor

Tumor adaptation
The glycolysis-based metabolic preferences of tumor cells (“Warburg Effect”) render lactate closely connected with tumor cell metabolism. Lactate also profoundly alters the TME through a series of sophisticated mechanisms. TAp73 enhances lactate metabolism through upregulation of PFKL (phosphofructokinase-1, liver type) and serves as a crucial upstream regulator in the mechanisms of lactate accumulation and lactate-associated tumor adaptation, making it an important molecular node linking tumor metabolic reprogramming to lactate accumulation [202].
First, the frontline of controlling lactate entry into the tumor lies in specific transporters, which predominate in lactate import and export. As explained above, both MCT1 and MCT4 play central roles in tumor metabolic activities. MCT1 exhibits relatively high affinity for lactate and primarily mediates its uptake under most tumor microenvironmental conditions. However, depending on the transmembrane H+/lactate gradients, MCT1 can also facilitate lactate efflux, particularly in cells with fluctuating metabolic demands. This bidirectional transport is not constant, but governed by dynamic proton-coupled concentration gradients [8, 43]. MCT4, which is abundantly found in cells with high glycolytic activity, primarily exports lactate due to its low affinity for the substrate. Then, the redundant lactate is transported to the extracellular matrix, assisting tumor cells in maintaining intracellular pH homeostasis [53].
Importantly, MCT1 has been identified as a functional and prognostic marker in multiple cancers. In osteosarcoma, MCT1 expression was confirmed across several cell lines and primary tumors. Inhibition of MCT1 significantly delayed tumor growth both in vitro and in vivo, including in orthotopic models. Notably, MCT1 blockade also enhanced the sensitivity of tumor cells to chemotherapeutics like adriamycin and suppressed their metastatic potential. Mechanistically, these antitumor effects were associated with suppression of the NF-κB pathway, and high MCT1 expression correlated with poorer overall survival in patients [203]. In addition to membrane transport, lactate also functions as a signaling molecule via its receptor GPR81 (HCAR1). Initially identified in adipose and muscle tissue, GPR81 is now recognized to be overexpressed in solid tumors, where it serves as a metabolic sensor for lactate. Silencing of GPR81 dramatically reduced tumor cell survival in lactate-supplemented, low-glucose conditions, suggesting its essential role in lactate utilization under nutrient stress. In vivo, GPR81 expression correlated with increased tumor growth and metastasis in pancreatic cancer models. Furthermore, GPR81 modulates the expression of lactate-handling genes such as MCT1/4, indicating its feedback control over both lactate signaling and transport [204]. These findings highlight the multifaceted roles of lactate in tumor adaptation, not only as a metabolic substrate but also as a signal integrator that coordinates energy metabolism and transport systems within the TME.

Tumor immunosuppression
In the TME, metabolic reprogramming not only provides energy and biosynthetic substrates to support the accelerated growth of tumor cells, but also significantly changes the local immune ecology. A prominent immunosuppressive characteristic is the accumulation of lactate due to elevated glycolysis, creating an acidic, lactate-enriched microenvironment that inhibits the proliferation, cytokine release, and cytotoxic activities of T cells and NK cells. This environment also promotes macrophage polarization towards a pro-tumor M2-like phenotype, thereby reducing anti-cancer immune responses [205–207]. Additionally, lactate contributes to metastatic regulation through epigenetic-related signaling. As previously discussed, lactate-driven M2 macrophage polarization also constitutes a key mechanism contributing to the immunosuppressive TME that facilitates tumor spread in breast cancer [95].
Beyond immunometabolic interference, lactate mediates immune suppression through epigenetic and receptor-mediated signaling mechanisms. For example, in colorectal cancer, elevated lactate levels induce H3K18 lactylation and direct lactylation of methyltransferase-like 3 (METTL3) at RNA-binding zinc-finger domains, enhancing its ability to catalyze m⁶A modification of JAK1 mRNA. This promotes YTHDF1-dependent translation, JAK1 upregulation, and downstream STAT3 activation, thereby reinforcing the immunosuppressive phenotype of tumor-infiltrating myeloid cells (TIMs) and promoting immune evasion [208]. These findings highlight the emerging role of non-histone lactylation in post-transcriptional gene regulation [96].
In parallel, lactate signals through its G-protein-coupled receptor GPR81 (HCAR1) to promote immune escape. In lung cancer cells, lactate activates GPR81, which reduces intracellular cAMP and inhibits PKA activity, leading to activation of the transcriptional coactivator TAZ. TAZ then interacts with TEAD transcription factors to induce PD-L1 expression, suppressing T cell activity. This lactate-GPR81-LDHA-TAZ-PD-L1 axis constitutes a key immunosuppressive circuit within the TME that mechanistically links metabolic reprogramming to immune evasion [209]. To visually summarize these mechanisms, Fig. 10 provides an integrated schematic of how lactate mediates metabolic coupling, epigenetic remodeling, and immune evasion in the TME. It highlights intercellular lactate shuttling, intracellular lactyl-CoA-driven protein lactylation, and the lactate-GPR81-TAZ-PD-L1 signaling axis that facilitates immunosuppression.

Lactate-induced extracellular acidosis further contributes to immunosuppression by impairing tumor-infiltrating lymphocyte (TIL) function and promoting tumor invasiveness [210]. Specifically, lactateosis inhibits cytokine production (such as IFN-γ) and partially blocks lysosomal granule efflux in cytotoxic T lymphocytes (CTLs). Mechanistically, it selectively suppresses JNK, c-Jun, and p38 phosphorylation while sparing MEK1 and ERK signaling, thus compromising CTL effector functions. Importantly, this immunosuppression is rapid and reversible, and buffering extracellular acidity can restore CTL function even in the presence of high lactate levels [211]. In light of these immunosuppressive effects, regulating lactate export has emerged as a potential therapeutic strategy. In light of these immunosuppressive effects, regulating lactate export has emerged as a potential therapeutic strategy. To handle lactate accumulation and maintain pH homeostasis, tumor cells upregulate lactate transporters such as MCT1 and MCT4, facilitating lactate efflux to avoid intracellular acidification [212]. Targeting these transporters with MCT inhibitors has been proposed as a therapeutic strategy to disrupt lactate recycling and tumor metabolism [67]. However, mathematical modeling suggests that MCT inhibition alone may not significantly decrease lactate production due to autoregulatory feedback on flux control [213]. Additionally, MCT1/4 contribute to immune dysfunction, angiogenesis, and chemoresistance through interactions with stromal components in the TME [38].
Interestingly, lactate may also play an immunostimulatory role under specific conditions. Kaymak et al. reported that moderate lactate concentrations can upregulate TCF-1 expression in CD8+ T cells, enhancing stem-like properties and memory potential, thereby prolonging antitumor responses [214]. These findings suggest that the immunoregulatory effects of lactate are highly context-dependent, influenced by concentration, extracellular pH, and microenvironmental cues. Therefore, it is crucial to distinguish between lactate itself and lactate-induced acidosis when assessing its role in immune modulation.

Tumor angiogenesis and metastasis
Lactate is a key byproduct of glycolytic activity in tumors and serves a significant function in regulating signaling within the TME. Increasing evidence indicates that lactate is essential for promoting angiogenesis in cancers, thereby driving tumor progression [215].
In terms of angiogenesis, lactate can enter vascular endothelial cells via MCT1, leading to IκBα phosphorylation and subsequent degradation, thereby activating the NF-κB pathway and upregulating IL-8 transcription, a key mediator of angiogenesis. This signaling axis enhances the motility of endothelial cells and lumen formation, and is an important driver of tumor neovascularization. Studies have also found that this process relies on the interplay between ROS and PHD signaling. More critically, in colorectal and breast cancer xenograft models, tumor cells activate this IL-8-dependent pathway by releasing lactate via MCT4, which promotes neovascularization and tumor growth. This suggests that the lactate/NF-κB/IL-8 pathway serves as a critical hub connecting tumor metabolic activity and angiogenic processes. Additionally, lactate enters vascular endothelial cells via MCT1, which can activate the HIF-1 pathway and upregulate the expression of VEGFR2 and bFGF under normoxic conditions, promoting angiogenesis. Blocking this process significantly inhibited tumor-associated neovascularization. This pathway demonstrates lactate’s function as an active signaling agent in angiogenesis and underscores the therapeutic potential of targeting MCT1 for both metabolic inhibition and suppression of neovascularization [216].
Lactate has also been involved in promoting the metastatic capacity of tumor cells by regulating intercellular adhesion, extracellular matrix degradation, and the establishment of a favorable microenvironment at metastatic sites. Researchers have found that extracellular acidification is linked with more aggressive tumor behaviors through upregulating ProMMP9/MMP9 expression, disrupting intercellular adhesion, and clearing obstacles for metastasis [217, 218]. The immunosuppressive nature of lactate impairs T-cell functionality and enables metastatic tumor cells to escape immune surveillance in secondary locations. It has also been observed that a high-lactate environment remodels the metabolic state of tumor-associated stromal cells, synergistically inducing angiogenesis, immunosuppression and metastatic stabilization, and setting the stage for distal metastasis [219]. In summary, lactate not only maintains the energy required for tumor growth by metabolic means, but also regulates angiogenesis and metastasis through a series of signaling pathways to provide structural and functional support for tumors. Therefore, interfering with lactate production or blocking its signaling pathway may become an effective strategy to inhibit abnormal tumor vascular development and distal metastasis (Fig. 11).

Therapeutic targeting of lactate metabolism
The central role of lactate in the metabolic reprogramming of the TME is well-established, acting as both a key byproduct of glycolytic metabolism and a crucial modulator of various cellular signaling networks. In recent years, therapeutic strategies targeting lactate metabolism have gained increasing attention, emerging as a critical avenue in metabolic therapy and immunomodulation. These strategies are applicable to cancer treatment and show promising potential for conditions such as ischemia/reperfusion injury, neurodegenerative disorders, and cardiovascular disease.

Tumor therapy
Considering lactate’s central function in metabolic reprogramming of the TME, lactate metabolism has emerged as a novel focus for tumor therapy. Therapeutic strategies targeting lactate metabolism fall into two major categories: direct modulators, which inhibit lactate production or transport by acting on LDHA/B or MCT1/4; and indirect modulators, which target upstream glycolytic regulators to reroute pyruvate toward mitochondrial oxidation or suppress hexokinase-mediated glycolysis [45, 220]. Notably, lactate transporters MCT1 and MCT4 require the chaperone protein CD147 (basigin) for membrane localization and functional activation. Inhibiting CD147, rather than MCTs directly, disrupts lactate transport by interfering with the disulfide-bonded domains in their Ig-like C2 region, highlighting its essential role in maintaining MCT catalytic activity [221].
A number of LDHA/B inhibitors, such as FX-11, Galloflavin, and N-hydroxyindole-based compounds, have been explored in animal or preclinical studies for cancer treatment, as summarized in Table 3. While some of these compounds have demonstrated anticancer activity in preclinical models, it is important to note that many, including galloflavin (largely abandoned due to poor bioavailability), have not progressed beyond this stage. Furthermore, the clinical translation of LDHA inhibitors as a class has been challenging, often hampered by issues of toxicity and lack of selectivity [222]. Therefore, while these preclinical findings are valuable for understanding LDHA as a target, their therapeutic readiness should not be overstated, and further research is crucial to assess their true clinical potential.

Similarly, several novel MCT1/4 inhibitors are under investigation, including AZD3965, which has demonstrated anti-tumor effects by inhibiting MCT1, disrupting lactate metabolism in tumors, and causing lactate accumulation within cancer cells. This leads to a decrease in intracellular pH, thereby inhibiting tumor cell growth and proliferation. Additionally, AZD3965 may affect the tumor microenvironment by disrupting the metabolic coupling between tumor cells and stromal cells. The Phase I clinical study confirmed the feasibility of this mechanism and laid the foundation for further research in tumor types with high MCT1 and low MCT4 expression, such as certain lymphomas. However, its true therapeutic efficacy will need to be further validated in biomarker-selected patient populations [67]. However, its true therapeutic efficacy will need to be further validated in biomarker-selected patient populations. Most of the other MCT1/4 inhibitors remain in preclinical stages and have not yet been tested in clinical trials, and further validation in clinical settings is required to establish their therapeutic potential [68, 69, 223].
Of note, targeting lactate production upstream represents a viable therapeutic strategy. This approach is exemplified by Dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase that diverts pyruvate away from lactate conversion and into mitochondria, and by Lonidamine, which suppresses glycolysis at its origin by inhibiting mitochondrially-bound hexokinase. Clinical studies have demonstrated the feasibility of both approaches, with oral DCA being well-tolerated in patients with recurrent malignant brain tumors and Lonidamine showing modest efficacy in a Phase II study for recurrent glioma, thereby providing a clinical foundation for targeting glycolytic flux to suppress tumorigenic lactate generation [224, 225].
Beyond modulating the metabolic and immune environments of tumors, targeting tumor matrix remodeling has emerged as a novel therapeutic strategy. CD147 (EMMPRIN) is a glycosylated membrane protein highly expressed on the surface of tumor cells. It induces the synthesis of matrix metalloproteinases (MMPs) through homodimeric binding and promotes tumor invasion. Blocking CD147 homophilic binding significantly inhibits MMP-2 secretion and tumor cell invasion, suggesting its potential as a target for anti-metastatic therapy [226]. Moreover, CD147 can directly enhance the angiogenic capacity of endothelial cells by upregulating hypoxia-inducible factor 2 alpha (HIF-2α), vascular endothelial growth factor receptor 2 (VEGFR-2), and soluble VEGF isoforms. This provides new insights into the mechanisms of CD147-mediated tumor angiogenesis and highlights CD147 as a potential target for anti-angiogenic therapies [227].
In recent years, the advantages of combining lactate inhibitors with immunotherapy in antitumor treatment have become increasingly evident. In particular, when used in conjunction with immune checkpoint inhibitors (ICIs) and Stimulator of Interferon Genes (STING) agonists, lactate inhibitors can significantly decrease tumor immunosuppression and promote the activation of tumor-infiltrating T cells [228, 229]. Through this combination strategy, the immune escape mechanism in the TME can be overcome and the immune system’s capacity to clear the tumor can be enhanced. This dual treatment approach enhances the durability and efficacy of immunotherapy. Consequently, the combined application of lactate inhibitors and immunotherapy shows great clinical promise and opens up new avenues for cancer treatment [230, 231]. Collectively, this evidence underscores the pivotal role of lactate in tumor progression and therapy, as illustrated in Fig. 11.

Therapeutic approaches for Non‑oncological conditions
As previously described, lactate has emerged as a vital mediator in various non-cancerous pathologies, where it functions as more than just a product of metabolism, serving as a signaling agent and modulating the microenvironment. Accordingly, a growing number of targeted intervention strategies have emerged, offering new therapeutic avenues and broad prospects for the treatment of non-tumor diseases.

Athletic performance and metabolic regulation
The role of lactate in facilitating exercise adaptation is rooted in its triple identity as an energy substrate, a signaling molecule, and, most recently, an epigenetic regulator. This multifaceted nature means that the lactate surge during exercise does not simply represent a metabolic byproduct; rather, it actively orchestrates a wide range of cellular and molecular responses that underpin long-term training adaptations [232].
As a central component of the cell-to-cell and intracellular lactate shuttles, lactate ensures efficient energy distribution from its production sites such as glycolytic muscle fibers to oxidative tissues, including heart, brain, and oxidative muscle fibers, where it serves as a primary fuel for mitochondrial oxidative phosphorylation [233, 234]. Long-term sodium lactate supplementation has been shown to increase mitochondrial enzyme activity in skeletal muscle, underscoring its role in mitochondrial adaptation during exercise [235]. Beyond its energetic role, lactate-derived lactylation has emerged as a key mechanism fine-tuning metabolic and adaptive processes. For instance, mitochondrial protein lactylation, such as on PDHA1 and CPT2, may transiently constrain oxidative metabolism during exhaustive exercise as a protective mechanism against oxidative damage [74].
Furthermore, lactate acts as a critical mediator along the muscle-brain axis. Exercise-induced lactate can cross the blood-brain barrier and be taken up by neurons and astrocytes. Critically, this circulatory lactate integrates into the well-established ANLS theory within the hippocampus, a process fundamental to learning and memory. Disruption of this lactate shuttle at either the astrocytic (MCT4) or neuronal (MCT2) level leads to spatial memory deficits, as demonstrated in hippocampus-dependent tasks. Notably, these impairments can be rescued by exogenous L-lactate in MCT4-deficient but not MCT2-deficient mice, indicating that lactate transfer from astrocytes and its utilization in neurons are both essential for memory acquisition. In addition, neuronal MCT2 plays a unique role in long-term memory consolidation, and its knockdown in mature neurons also impairs hippocampal neurogenesis, revealing that MCT2 function extends beyond metabolic support to the regulation of plasticity-related processes. These findings underscore the indispensable and distinct roles of astroglial MCT4 and neuronal MCT2 in lactate-mediated cognitive function [47, 236].
However, the signaling cascade that triggers lactate release for memory consolidation is sophisticated. It is initiated by emotionally salient experiences that engage noradrenaline, which then acts specifically on hippocampal astrocytic β2-adrenergic receptors (β2ARs) [237]. This receptor activation is coupled to the training-dependent release of lactate from astrocytes, which is necessary for both long-term memory formation and the underlying molecular changes, such as the induction of phospho-CREB and Arc [47, 237]. Furthermore, optogenetic studies demonstrate that increasing cAMP levels specifically in hippocampal astrocytes is sufficient to modulate memory, an effect that is mediated by ANLS[238]. Building on these findings, the lactate surge induced by exercise is poised to emulate or augment these endogenous neurochemical processes. By supplying a supplementary flux of lactate to the brain, exercise may directly fuel the as ANLS, thereby facilitating the synaptic plasticity, gene expression, and neurogenesis that underlie the acquisition and consolidation of long-term memory [47, 236]. This establishes lactate as a pivotal molecular link that translates physical activity into enhanced cognitive function.
In parallel, the potential of oral lactate as a nutraceutical has garnered interest. Serving as a key energy source, signaling agent, and metabolic regulator, oral lactate is quickly absorbed into the bloodstream and skeletal muscles, enhancing oxidative metabolism [239]. In the liver, it may be transformed into glucose and stored as glycogen, while consuming hydrogen ions to help maintain bicarbonate levels and enhance extracellular pH buffering [233]. Therefore, lactate supports energy production and acid-base balance during exercise. Recent studies further suggest that lactate supplementation may enhance mitochondrial enzyme activity in oxidative muscle, thereby improving mitochondrial function [235]. Nevertheless, its physiological impacts appear to be multifaceted and context-sensitive, highlighting the need for further targeted investigation. While lactate exhibits clear buffering properties by increasing blood pH and bicarbonate levels, beneficial in short-duration, high-intensity efforts, it fails to improve endurance performance under lower-intensity or prolonged exercise conditions [240]. This dualistic outcome likely stems from the distinct physiological roles of lactate and associated acidosis: elevated lactate itself may not impair muscle function and might even support performance, yet the concomitant severe intracellular acidosis (pH 6.5–6.2), especially in fast-twitch fibers, reduces calcium sensitivity and impairs myosin ATPase activity, ultimately inducing muscle fatigue. Such conflicting observations are exemplified in studies where lactate supplementation improved acid-base balance and lowered perceived exertion without enhancing actual performance output. For instance, one trial on high-intensity interval cycling reported no performance gains despite improved buffering [241]. Similarly, another clinical study involving recreational exercisers found that oral lactate failed to improve aerobic capacity or lactate threshold, though it modestly increased work rate during a 20-minute time trial [242]. These findings underscore the importance of context, dosage regimen, and metabolic environment, reinforcing that the systemic benefits of lactate may be counteracted by localized biochemical disturbances in muscle tissue.

The lactate-microbiome-host axis
The regulatory role of lactate extends beyond cellular metabolism and systemic signaling to encompass profound influence on the gut ecosystem. This is evidenced by its significant prebiotic potential in shaping gut microbiota composition. A comprehensive meta-analysis reveals that lactate supplementation selectively enriches beneficial gut bacteria, such as Lactobacillus and Bifidobacterium, while reducing the Firmicutes-to-Bacteroidetes ratio and suppressing potential pathogens like Clostridium. Critically, these effects exhibit a clear dose-dependency, with pronounced benefits for Lactobacillus at doses exceeding 2,000 mg/day and for Bifidobacterium across a wide range (10 − 5,500 mg/day). Moreover, the response is age-dependent, with young adults demonstrating more consistent and robust improvements compared to older adults. This positions lactate as a promising agent for improving gut health and microbial balance [243].
The pivotal role of lactate-producing and consuming bacteria in gut and systemic health is particularly evident in the context of inflammatory bowel disease (IBD). Lactate-producing bacteria, such as Lactobacillus and Bifidobacterium, play a key role in the human gut microbiota and have shown effectiveness in alleviating IBD by improving intestinal permeability, reducing inflammation, and importantly, influencing the composition of the gut microbial community [244, 245]. A key mechanism underpinning their benefit is microbial cross-feeding. Lactate produced by bacterial community serves as a critical energy substrate for other commensal bacteria, such as butyrate-producing species within Clostridium groups XIVa and IV (e.g., Faecalibacterium and Roseburia) [246, 247]. This lactate-to-butyrate metabolic pathway is essential for maintaining colonic health, as butyrate serves as a primary energy source for colonocytes, strengthens the epithelial barrier, and exerts potent anti-inflammatory effects [248].
Conversely, dysbiosis in IBD is characterized by a depletion of these beneficial short-chain fatty acid (SCFA)-producing bacteria and an expansion of potential pathobionts like Escherichia coli [249, 250]. Interventions with specific lactate-producing strains, such as Levilactobacillus brevis and Lactobacillus paracasei, have been shown to counteract this dysbiosis by increasing the abundance of SCFA-producing bacteria and reducing pro-inflammatory cytokines, thereby restoring a healthier microbial ecosystem and alleviating colitis [247, 248]. Therefore, the therapeutic potential of lactate and lactate-producing bacterial community extends beyond their direct actions, lying significantly in their capacity to nourish a cooperative microbial network through cross-feeding, which collectively stabilizes gut homeostasis and immune function.

Other diseases
Lactate metabolism plays diverse roles across a range of diseases beyond cancer, including cardiovascular, neurological, metabolic, and inflammatory conditions. In ischemia-reperfusion injury, lactate supports neuronal survival via ANLS and histone lactylation modulation [13, 49, 251]. In obesity-associated insulin resistance, lactate accumulation due to impaired MCT1-mediated efflux contributes to inflammation and adipocyte dysfunction [144, 252]. In cardiovascular disease, lactate exerts both metabolic and signaling effects, while in epilepsy, LDH inhibitors targeting astrocyte-derived lactate have demonstrated anti-seizure activity approved by the U.S. Food and Drug Administration (FDA) [68, 136–139, 253]. Therapeutic strategies involving lactate modulation have shown promising effects across these disease contexts, and a summary of representative lactate-targeted therapies across multiple disease models is provided in Table 3.

Conclusive remarks
Lactate was once thought to be just a byproduct of metabolism; however, with advancements in molecular biology and immunometabolism, growing evidence now shows that lactate plays essential and diverse roles in supporting human health and regulating disease mechanisms. From a basic substrate of energy metabolism to a key epigenetic regulator, from a guardian of physiological homeostasis to a promoter of disease development, the biological functions of lactate are far beyond the traditional understanding.
Under physiological conditions, lactate is not only a supplementary energy source for OXPHOS in muscle, brain, liver and other tissues, but also transmits metabolic information between cells through the lactate shuttle to maintain redox homeostasis. Lactate can move in and out of cells via MCTs, enter mitochondria to take part in the TCA cycle or be reprocessed in the liver through the Cori cycle; in addition, it acts on histones and non-histone proteins via lactylation modifications to play epigenetic regulatory roles in inflammatory repair, embryonic development and immune cell reprogramming.
Under pathological conditions, lactate accumulation and metabolic reprogramming have been increasingly recognized as critical contributors to a wide range of human diseases. Elevated lactate levels are observed not limited to tumors, but also widespread in various non-tumor diseases such as immune, cardiovascular, metabolic, neurological and infectious diseases. In these contexts, lactate is no longer simply a metabolic by-product, but a crucial element affecting disease evolution, prognosis and systemic homeostasis. Abnormal lactate levels are closely associated with chronic inflammation, tissue hypoxia, metabolic imbalance, and impaired immune regulation, highlighting its potential as a disease marker and regulator.
In conclusion, while the multifaceted roles of lactate in physiology and disease are increasingly clear from preclinical work, a significant translational gap remains. Future research must not only deepen our mechanistic understanding but also prioritize rigorous human studies to evaluate the safety and efficacy of lactate-targeted therapies. Bridging this gap is the essential next step to harnessing the biology of lactate for clinical benefit.