Metabolic reprogramming of astrocytes: Emerging roles of lactate

Abstract

Lactate serves as a key energy metabolite in the central nervous system, facilitating essential brain functions, including energy supply, signaling, and epigenetic modulation. Moreover, it links epigenetic modifications with metabolic reprogramming. Nonetheless, the specific mechanisms and roles of this connection in astrocytes remain unclear. Therefore, this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system. The close relationship between epigenetic modifications and metabolic reprogramming was discussed. Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases. In the nervous system, lactate plays an essential role. However, its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation. The involvement of lactate in epigenetic modifications is currently a hot research topic, especially in lactylation modification, a key determinant in this process. Lactate also indirectly regulates various epigenetic modifications, such as N6-methyladenosine, acetylation, ubiquitination, and phosphorylation modifications, which are closely linked to several neurological disorders. In addition, exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.

Introduction

The brain consumes approximately 20% of the total energy in the body, necessitating a high metabolic rate for its development and function (Bélanger et al., 2011a). Glucose supplies energy to the brain primarily via metabolic reprogramming, with astrocytes playing a fundamental role in this process (Allen and Lyons, 2018). Astrocytic metabolic reprogramming involves adjusting metabolic processes, such as glycolysis, fatty acid metabolism, amino acid metabolism, and oxidative phosphorylation, in response to changes in the microenvironment and demands of glial cell, neuron growth, and metabolic processes (Xiong et al., 2022b). In this process, astrocytes may mediate energy supply and signaling through metabolic reprogramming to increase lactate production, facilitating their involvement in disease progression (Calì et al., 2024). Astrocytes promote the transport of glutamate, lactate, and high-energy ATP phosphate through carriers, channels, and exocytosis, playing critical roles in maintaining central nervous system (CNS) homeostasis, forming neuronal synapses, repairing nerve damage, and regulating axonal excitability (Ransom and Kettenmann, 2020). Astrocytes exhibit greater metabolic plasticity than neurons despite the inherent heterogeneity in their cellular metabolism. Astrocytes primarily produce excessive lactate under aerobic conditions, while neurons mainly rely on oxidative phosphorylation (OXPHOS) for energy metabolism (Supplie et al., 2017; Barros et al., 2021). Consequently, astrocytes can mediate metabolic reprogramming in the CNS when faced with significant challenges (Lee et al., 2022).

Astrocytes are also the primary cells responsible for lactate secretion in the CNS (Magistretti and Allaman, 2018). In mammals, lactate exists as two stereoisomers, i.e., L-lactate and D-lactate, with L-lactate being the predominant form generated during glycolysis (Manosalva et al., 2021). Lactate is the preferred metabolite over glucose in the CNS during high-energy demanding tasks (Riske et al., 2017). Furthermore, lactate is a pleiotropic signaling molecule that modulates axonal regeneration, immune-inflammatory responses, and neural plasticity. Astrocytes produce lactate via two primary pathways, i.e., glycogenolysis and glycolysis. Glycogenolysis is induced by activity-dependent neural signals, including norepinephrine, adenosine, and potassium (K⁺). In contrast, glycolysis is primarily initiated by glutamate, K⁺, and nitric oxide (Pellerin and Magistretti, 1994; Lerchundi et al., 2015). However, current reviews addressing the link between lactate-mediated astrocyte metabolic reprogramming and epigenetic modifications are limited, and the specific molecular mechanisms by which they mediate epigenetics remain to be explored in depth. Therefore, this review aims to examine the role and mechanism of lactate-mediated metabolic reprogramming in astrocytes and explores the role of lactate in linking metabolic reprogramming to epigenetic modifications. This review also provides new ideas for drug development targeting astrocyte metabolic reprogramming in neurological diseases.

Search Strategy

Studies cited in this narrative review were published from 1985 to 2024, with most published from 2019 to 2024. All studies cited were sourced from the PubMed database using the following keywords: lactate, astrocyte, oligodendrocyte, monocarboxylate transporters, axonal regeneration, metabolism, glycolysis, lactate shuttle, neurodegenerative diseases, injury, inflammation, neural synaptic plasticity, learning and memory, epigenetic, histone lactylation, N6-methyladenosine (m6A), ubiquitination, acetylation, Alzheimer’s disease (AD), Parkinson’s disease (PD), ischemic encephalopathy, and fear. Figure 1 illustrates the timeline of literature sources associated with lactate and the nervous system.

Figure 1.

Timeline of literature sources associated with lactate and the nervous system.

Created with BioRender.com.

Astrocytes as the Main “Producers” of Lactate

Astrocytes play a crucial role in mediating glucose uptake and energy demands in the resting state of the CNS (Chuquet et al., 2010; Feng et al., 2024; Tyurikova, 2024; Xu et al., 2024). Despite the availability of oxygen under aerobic conditions, astrocytes predominantly convert glucose to lactate. This preference results from cell-specific gene expression profiles that promote glycolysis, even in the presence of oxygen (Bouzier-Sore and Pellerin, 2013). High expression of the glycolytic enzyme PFKFB3 in astrocytes is crucial in this process, activating phosphofructokinase (PFK) via 6-phosphofructokinase 2-kinase (F-2,6-P), thereby improving glycolysis. In addition, pyruvate kinase 2 (PKM2), specifically expressed in astrocytes, further promotes glycolysis and mediates metabolic reprogramming (Magistretti and Allaman, 2015). Another regulation layer arises from the expression of pyruvate dehydrogenase kinase 4 (PDK4) in astrocytes, which suppresses pyruvate dehydrogenase (PDH). This inhibition leads to PDH phosphorylation, preventing pyruvate from entering the tricarboxylic acid cycle (TCA) and promoting lactate production via glycolysis (Boison and Steinhäuser, 2018). Moreover, astrocytes are capable of managing the by-products of glycolysis, including methylglyoxal, a reactive dicarbonyl compound. The high expression of glutathione enzyme 1 and glutathione enzyme 2 in astrocytes enhances their resilience against methylglyoxal accumulation, allowing them to sustain glycolysis without interruption (Bélanger et al., 2011b).

Lactate Shuttle “Networks” in the Central Nervous System

The concept of lactate shuttle ‘networks’ reveals an important transduction mechanism of lactate as an energy substrate and signaling molecule in the CNS. It is applicable to a wide range of disease progression and pathophysiologic processes in the CNS. The lactate shuttle ‘network’ involves astrocytes as ‘transmitters,’ neurons and other glial cells as ‘receivers,’ and monocarboxylate transporters (MCTs) as ‘vehicles.’ This ‘network’ facilitates the efficient transport of lactate throughout the nervous system (Figure 2).

Figure 2.

Lactate mediates network formation in the central nervous system.

Glucose is primarily absorbed by GLUT1 in astrocytes and converted into lactate through glycogenolysis and glycolysis. These metabolic pathways are induced by K⁺, NA, ADO, NO, and glutamate, respectively. Lactate is primarily transported within astrocytes by MCT1 and MCT4, while oligodendrocytes and neurons predominantly use MCT1 and MCT2 for lactate uptake, respectively. Additionally, astrocytes and oligodendrocytes are interconnected via connexins CX30/32 and CX43/47, forming a dynamic interactive network with neurons. Furthermore, the ANLS promotes metabolic coupling and expression of synaptic plasticity-associated proteins, including CREB, cFos, Zif268, BDNF, Arc, and Arg. Created with BioRender.com. ADO: Adenosine; ANLS: astrocyte-neuronal lactate shuttle; BDNF: brain-derived neurotrophic factor; K⁺: potassium; MCT: monocarboxylate transporter; NA: norepinephrine; NO: nitric oxide.

Astrocyte–oligodendrocyte–neuron interaction in lactate shuttle network formation

Brooks proposed the lactate shuttle hypothesis in the early 1980s and coined the term ”lactate shuttle” in 1986, which involves intercellular, intracellular, and interorgan lactate shuttles. This concept highlights the role of lactate as an oxidative and a metabolic substrate as well as a signaling pathway (Brooks, 2009, 2018). The astrocyte-neuronal lactate shuttle (ANLS) is a crucial system that connects neuronal activity to energy transfer. It is prevalent in various regions of the CNS, particularly in myelinated axons. However, lactate cannot be directly used as an energy source in the CNS (Barros et al., 2020). It is primarily generated within astrocytes and then used to meet the OXPHOS demands of neurons via the ANLS (Magistretti and Allaman, 2018). However, studies show that the lactate shuttle extends beyond just astrocytes and neurons. Astrocytes can transfer lactate to oligodendrocytes, which then support neuronal activity. This broader metabolic network, which involves astrocytes, oligodendrocytes, and neurons, enhances energy coupling efficiency in the CNS based on the ANLS model (Amaral et al., 2013; Barros et al., 2018).

Gap junctions in the CNS form not only between astrocytes but also between astrocytes and oligodendrocytes. These junctions involve astrocyte connexins Cx30 and Cx43, which connect to oligodendrocyte connexins Cx32 and Cx47, respectively. This interaction forms CNS networks, including Cx47–Cx30, Cx32–Cx26, Cx32–Cx30, and Cx47–Cx43 (Magnotti et al., 2011). Studies show that mice lacking Cx32 and Cx47 develop serious CNS demyelination, tremors, axonal damage, and seizures. Additionally, Cx43 knockdown in astrocytes alters glucose delivery to oligodendrocytes, suppresses their proliferation, and affects the metabolic reprogramming of astrocytes (Rinholm et al., 2011). Other studies show that the pathogenesis of multiple sclerosis is mainly associated with the loss of early oligodendrocyte metabolic reprogramming, followed by astrocyte activation. This process involves the downregulation of connexins Cx32 and Cx47 in oligodendrocytes, along with the upregulation of connexin Cx43 in astrocytes (Nikić et al., 2011).

Role of monocarboxylate transporters in lactate shuttle network formation

The ANLS primarily relies on monocarboxylate transporters (MCTs) to function in the CNS. These transporters, which include MCT1, MCT2, and MCT4, play key roles in transporting monocarboxylates, including pyruvate, lactate, and ketone bodies across membranes, driven by their concentration gradients. MCT1 (SLC16A1) exhibits the highest affinity for lactate, followed by MCT2 (SLC16A7) with moderate affinity, and MCT4 (SLC16A3) with the lowest (Philips and Rothstein, 2017). The activity of these MCTs also depends on accessory proteins present, including Basigin, Embigin, and Neuroticin (Ovens et al., 2010).

MCT expression in the CNS varies according to cell types. For instance, astrocytes and oligodendrocytes express MCT1, enabling bidirectional lactate transport. This transport capacity facilitates metabolic exchanges within glial cells and around axons, enhancing neuronal metabolic support (Saab and Nave, 2016). MCT1 downregulation can induce severe neuronal damage and inhibit axonal regeneration (Philips et al., 2021). In experimental models, injecting MCT1 shRNA into the spinal cord causes motor neuron injury and axonal degeneration, which are reversible with lactate administration. Reduced MCT1 expression and lactate release from glial cells correlate with motor neuron degeneration in amyotrophic lateral sclerosis, implicating glial MCT1 in the pathogenesis of this neurodegenerative disease (Philips et al., 2013).

MCT2, predominantly found in neurons and endothelial cells, influences metabolic processes by interacting with the lactate receptor HCAR1, which suppresses cAMP production. This inhibition improves glycolysis while reducing lactate production, thereby decreasing the energy availability for myelination. Maintaining optimal cAMP levels in the CNS is crucial for adaptive responses to cellular and external environmental changes, supporting both global and local nervous systems (Arnsten et al., 2012).

Astrocytes-derived lactate also activates GABA receptors on neurons, stimulating intracellular cAMP (Morrison et al., 2015). Conversely, in AD models, upregulated MCT4 expression in astrocytes correlates with impaired neurite outgrowth and increased apoptosis (Hong et al., 2020). In vivo, MCT1 is essential for basal lactate release, while MCT4 predominantly enhances lactate release during activity. Lactate transport direction is accurately regulated by the distribution of MCTs within each cell and their redox status, ensuring that lactate is transported along the concentration gradient to the extracellular space (Fünfschilling et al., 2012).

These studies show that targeting MCTs in CNS astrocytes regulates metabolic reprogramming, modulating lactate production. Nevertheless, the absence of specific antagonists or agonists for MCTs presents a challenge. Thus, investigating the specificity of MCTs could offer significant potential as a treatment strategy.

Lactate-Mediated Metabolic Reprogramming Performs Multiple “Duties”

Lactate-mediated metabolic reprogramming of astrocytes can act as a ‘regenerator’ of axons

In the CNS, lactate serves as an energy source for neurons and regulates axonal integrity (Bonvento and Bolaños, 2021). Achieving axonal regeneration following CNS injury or in neurodegenerative diseases poses a significant challenge. Axonal regeneration requires significant metabolic energy, and the metabolic reprogramming of astrocytes enhances this process by supplying energy and signaling molecules to neurons. However, local energy depletion significantly hinders axonal regeneration following neuronal injury (Silver and Miller, 2004; Curcio and Bradke, 2018; Li et al., 2020).

In addition, Na⁺ channels can interact with endothelin receptors, leading to endothelin-mediated activation of Na⁺/K⁺-ATPase and subsequent lactate release, which promotes axonal regeneration. Lactate transport suppression significantly reduces ATP levels, highlighting the dependence of neuronal electrophysiological activity on lactate metabolism, even in the presence of glucose (Trevisiol et al., 2017). Moreover, lactate restores field post-synaptic potential in astrocytes exposed to glucose-oxygen deprivation (Philippot et al., 2021). Activation of pathways, including PI3K, EGFR, or the cell cycle in astrocytes triggers a regenerative state conducive to axonal regeneration, primarily via metabolic reprogramming that increases lactate production (Li et al., 2020). Nonetheless, the sustained increase of lactate metabolism within neurons elevates ROS production, which ultimately destabilizes axons (Jia et al., 2021).

Lactate may also improve axonal regeneration by acting as a substantial signaling molecule within the CNS (Magistretti and Allaman, 2018). The interaction between lactate and neurons involves NADH and ATP-mediated redox reactions that influence cellular energy dynamics. Lactate facilitates signal transduction via transport through MCTs and it is converted into pyruvate by lactate dehydrogenase, which subsequently enters the TCA cycle and maintains neuronal energy homeostasis. The lactate-to-pyruvate ratio, which reflects the cellular NAD⁺/NADH balance, is regulated by factors influencing external homeostasis (Yang et al., 2014).

Lactate-mediated metabolic reprogramming is involved in axonal regeneration in neurodegenerative diseases

Disturbances in cerebral energy homeostasis and metabolism are evident in the brains of patients with AD. This condition is characterized by elevated levels of biomarkers, including total tau and phosphorylated tau, as well as decreased lactate concentrations. This suggests a strong link between AD pathology and metabolic reprogramming (Liguori et al., 2015). Research shows that fibroblast growth factor 21 (FGF21) influences sympathetic nerve activity and energy expenditure in the CNS via receptor interactions. This may play a therapeutic role in early AD by regulating lactate shuttling between astrocytes and neurons. Furthermore, lactate shuttling may mitigate metabolic reprogramming deficits and Aβ-induced cytotoxicity via mechanisms including FGF21-induced autophagy, improving the neuroprotective effects of FGF21 (Sun et al., 2020).

Glucagon-like peptide-1 increases lactate accumulation via the PI3K/AKT pathway, which downregulates OXPHOS and reduces oxidative stress. AKT phosphorylation activates the mTOR and HIF-1α pathways, improving glycolysis in astrocytes of AD mice and significantly promoting neuronal survival and axonal regeneration (Zheng et al., 2021). AD progression is also linked to increased amyloid deposition, which disrupts the morphology and function of astrocytes (Ge et al., 2024; Lozupone and Panza, 2024). These reactive astrocytes exhibit downregulated expression of excitatory amino acid transporters EAAT1 and EAAT2, along with glucose transporter 1, leading to impaired glucose metabolism and neuronal damage. Activation of the α7 nicotinic acetylcholine receptor (α7nAChR) stimulates glutamate release and improves glutamate clearance, which increases extracellular lactate levels by activating the ANLS. This process helps in mitigating bioenergetic dysfunction in AD (Hascup et al., 2022).

Additionally, studies show that the expression of apolipoprotein E4 (APOE4)—the strongest and most common genetic risk factor for AD—increases glycolytic activity and lactate production in astrocytes following Aβ stimulation. Nonetheless, the resultant oxidative stress reduces neuronal support, highlighting the critical relationship between AD progression and astrocyte metabolic reprogramming (Farmer et al., 2021; Fleeman et al., 2023).

Lactate-mediated metabolic reprogramming is involved in axonal regeneration in the injury

Following traumatic brain injury (TBI), the primary energy source of the brain transitions from glucose to lactate (Glenn et al., 2015). Lactate demonstrates potential in managing traumatic and ischemic brain injuries as both a neuronal metabolite and signaling molecule via the lactate receptor GPR81 (HCA1). Lactate also exhibits significant neuroprotective effects during post-injury treatment (Roumes et al., 2021; D’Souza et al., 2022). Lactate production after brain injury also reduces oxidative damage induced by mitochondrial respiration (McKee et al., 2015).

Additionally, energy metabolism is disrupted after spinal cord injury (SCI), leading to decreased glucose absorption and utilization by spinal cord cells. Reprogramming astrocyte energy metabolism enhances glycolysis, increases lactate secretion, and activates the GABA-β receptors in neurons. Additionally, activated cAMP signaling promotes axonal regeneration in injured neurons. Moreover, administering exogenous lactate through local intrathecal injections significantly enhances axonal regeneration and improves motor function recovery in SCI mice (Li et al., 2020).

Lactate-mediated metabolic reprogramming of astrocytes is involved in the inflammatory response

In the CNS, acute and chronic inflammatory signaling triggers hypoxia, oxidative stress, and neurotoxicity. This inflammation causes neuronal death, damage to the blood–brain barrier, and demyelination (Guttenplan et al., 2021; Hasel et al., 2021). Microglia and astrocytes, regarded as innate immune cells within the CNS, play pivotal roles in neuroinflammation. Astrocytes actively participate in immune responses by secreting cytokines and chemokines as well as engaging in adaptive immune processes (Sofroniew, 2015). Activated astrocytes, i.e., reactive astrocytes, are mainly characterized by increased glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Their response to inflammation is closely associated with metabolic reprogramming, which may mediate the inflammatory response (Zhang et al., 2024b).

Nonetheless, the role of the metabolite lactate in these processes remains ambiguous; it could be anti-inflammatory or pro-inflammatory, depending on the target. Research shows that lactate causes signals to suppress acute inflammation while activating chronic inflammation (Manosalva et al., 2021). For instance, in a co-culture system of astrocytes and neurons, the ANLS increases lactate levels in neurons while reducing them in astrocytes following inflammatory stimulation (Wang et al., 2022c). Acute inflammation improves glucose absorption, PFK1 activity, and lactate production, while modulation of lactate metabolism reduces IL-1β and S100B secretion (Vizuete et al., 2022).

Additionally, studies show that stimulation with IL-1β and TNF-α significantly upregulates the gene expression of MCT4, PKM2, and GLUT1 in astrocytes, increasing glycolytic activity and decreasing oxidative phosphorylation, which enhances lactate production (Pamies et al., 2021). In contrast, in aging mice, activation of nuclear factor κB (NF-κB) in astrocytes is associated with improved aerobic metabolism (Jiang and Cadenas, 2014). A study using primary astrocytes from mice shows that inhibiting NF-κB signaling with inhibitor TPCA-1 disrupts metabolic reprogramming, reduces cytokine and chemokine secretion by inhibiting glycolysis, and hinders NF-κB phosphorylation. This highlights a strong connection between inflammation and glycolysis (Robb et al., 2020).

Moreover, lactate exhibits neuroprotective effects by mitigating the increase in intracellular calcium concentrations in neurons and astrocytes during oxygen-glucose deprivation, thereby slowing cell death and reducing the expression of pro-inflammatory cytokines and chemokines induced by oxygen-glucose deprivation or LPS (Babenko et al., 2024).

In addition, research shows that the hypothalamic PDK2-lactate axis regulates metabolic imbalance and hypothalamic inflammation, mediated via the AMPK signaling pathway and circuits that control feeding behavior. In diabetic mice, improved expression of PDK2 and phosphorylated PDH in the hypothalamus shifts glycolytic metabolism. In contrast, PDK2 inhibition in astrocytes significantly attenuates diabetes-induced hypothalamic inflammation, lowers lactate levels, and normalizes abnormal feeding behavior (Rahman et al., 2020). In the diabetic middle dorsal root ganglion, satellite glial cells are the primary expression of lipid carrier protein-2 (LCN2), an acute-phase pro-inflammatory protein that exacerbates neuroinflammation and neurotoxicity via the LCN2-PPARβ/delta-PDK2-lactate axis, thereby contributing to diabetic peripheral neurological pathology (Bhusal et al., 2021; Figure 3).

Figure 3.

Lactate-mediated inflammation in astrocytes.

Elevated lactate levels in astrocytes induce NDRG2 expression, reducing c-jun phosphorylation, and downregulating TNF-α expression, thereby disrupting the local microenvironment. TNF-α stimulation enhances the expression of MCT4, PKM2, and GLUT1 in astrocytes, increasing glycolytic activity. Conversely, inhibiting lactate production impairs NF-κB phosphorylation and the inflammatory response. The NF-κB inhibitor TPCA-1 also influences astrocytic metabolic reprogramming. Created with BioRender.com. MCT: Monocarboxylate transporter; NF-κB: nuclear factor kappa B; PKM2: pyruvate kinase 2; TNF-α: tumor necrosis factor-α.

Lactate-mediated metabolic reprogramming of astrocytes regulates neural synaptic plasticity

Synaptic plasticity is the ability of nerve cells to modulate the strength of their connections, which is crucial for cognitive activities, including learning and memory. It encompasses short- and long-term forms of plasticity. Memory, which is important for survival, involves the ability to retain and recall learned information. In the CNS, glial cells, specifically astrocytes, play significant roles in memory processing and storage by regulating vesicle release, synaptic function, and receptor signaling pathways (Han et al., 2012; Bazargani and Attwell, 2016).

The promotion of glycogenolysis and lactate release in astrocytes facilitates memory formation (Suzuki et al., 2011), while disrupting lactate shuttling between astrocytes and neurons impairs memory formation and consolidation (Ebersole et al., 2021). Aquaporin-4, primarily a water channel in astrocytes, influences learning and memory by regulating lactate transporters in the ANLS (Cha et al., 2023). In addition, Gi pathway activation in astrocytes in the anterior cingulate cortex (ACC) reduces intracellular cAMP and lactate levels, impairing memory recovery. This loss can be restored via the co-administration of exogenous lactate, promoting the expression of protein translation and synaptic plasticity-related genes, including p-CREB, CREB, and Erk1/2, and improves NMDA receptor signaling (Iqbal et al., 2022; Akter et al., 2023).

Studies show that the downregulation of the lactate transporters MCT2 and MCT4 blocks memory formation, a process that is reversible with lactate supplementation, which also induces MCT1 expression. Conversely, MCT1 depletion impairs long-term memory formation (Mächler et al., 2016; Chen et al., 2023). In addition, intraventricular administration of phosphoenolpyruvate carboxykinase, an essential enzyme in lactate metabolism, combined with selective inhibitors of lactate transporters, promotes the proliferation and differentiation of neuronal precursor cells (Álvarez et al., 2016).

Disrupting lactate production impairs memory consolidation and storage during training in rats, whereas β2AR knockdown in astrocytes induces memory loss, which is reversible with lactate (Gao et al., 2016). In Mlc-1-bPAC mice, stimulation enhances cAMP in astrocytes, activating ANLS. This improves NMDA receptor activity, subsequently boosting c-fos expression in neurons, critical for memory development (Choi et al., 2012; Jourdain et al., 2018). cAMP also maintains long-term potentiation (LTP) critical for memory formation, encoding new memories into long-lasting ones. LTP abnormalities include impairments in NMDA receptor-dependent and brain-derived neurotrophic factor-dependent synaptic plasticity (Li et al., 2012; Zhou et al., 2021).

Furthermore, ANLS and glycogen metabolism trigger the expression of various proteins responsible for memory formation, including CREB, c-fos, Zif268, NPAS4, brain-derived neurotrophic factor, and apoptosis-related proteins Arc, Arg, and pcofilin. This highlights the fundamental mechanisms driving synaptic plasticity and memory formation (Alberini, 2009; Gao et al., 2016; Sun and Lin, 2016; El Hayek et al., 2019; Figure 2). Disrupting lactate synthesis decreases the levels of memory formation–related proteins p-ERK1/2, Glua1, and Glua2. However, exogenous lactate reverses this effect (Zhang et al., 2016). Lactate also regulates redox via the NADH/NAD⁺ ratio, enhancing NMDA receptor activity in low redox conditions. This consequently, influences transcription factors, calcium signaling, and protein activity, crucial for memory formation and consolidation (Massaad and Klann, 2011; Yang et al., 2014).

Lactate as a bridge between metabolic reprogramming and epigenetic modifications

Besides its role in metabolic reprogramming, lactate influences transcription via epigenetic modifications, highlighting an important aspect of its functionality (Li et al., 2022; Yang et al., 2024). Therefore, lactate serves as a pivotal link between epigenetic modifications and metabolic reprogramming. Chromatin, comprising DNA and proteins, serves as a critical regulator of the genome. Various types of chromatin modifications, such as lactylation, methylation, ubiquitination, phosphorylation, and acetylation, promote the formation of specific transcriptional machinery. These epigenetic modifications significantly influence various processes, including gene expression and DNA replication (Izzo and Wellen, 2019). In neurological disorders, these modifications can affect neuroplasticity, neural specificity, and nerve functional recovery (Zhao et al., 2024). An in-depth exploration of the association between lactate and these modifications in the nervous system, as well as whether lactate participates in their dynamic regulation, remains an exploratory question.

Relationship between lactate and lactylation

Discovery of lactylation

In 2019, Zhang et al. introduced a novel histone acylation code called histone lactylation, marking a significant advancement in our understanding of epigenetic modifications influenced by cellular metabolism. Histone lactylation modifies histone proteins, altering chromatin structure and regulating gene expression. It is linked to various pathological conditions, such as tumors, inflammation, and neural excitability, elucidating the underlying molecular mechanisms that connect metabolic reprogramming with epigenetic modification (Li et al., 2022; Pan et al., 2022a; Wang et al., 2023a). Research indicates that lactate production is a vital determinant of histone lactylation levels, with the extent of lactylation closely linked to lactate concentration. Lysine lactylation levels decrease following lactate depletion, which can be triggered by adding glycolytic inhibitors. In addition, in the absence of lactate dehydrogenase, a vital enzyme in glycolysis, lysine lactylation also becomes diminished (Zhang et al., 2019).

Lactylation occurs beyond histones to non-histone proteins, although lactoyl substitution on lysine residues of non-histone proteins is less likely to occur. A significant proportion of lactonated proteins are localized in the nucleus (36%), mitochondria (27%), and cytoplasm (25%) in the bacterium Staphylococcus aureus, where they participate in various cellular processes. Forty-three lactonated ribosomal proteins in Staphylococcus aureus modulate protein translation and ribosome assembly (Gao et al., 2020). Similarly, several lactonated proteins in protozoan parasites participate in processes including trans-splicing, cap binding, RNA export, translation, and degradation. Several key glycolytic enzymes, such as ALDO, PGK, and PYK, can undergo lactonation (Zhao et al., 2022). Lactylation also directly influences the CCCH-type zinc finger structural domain of the human METTL3 protein, thereby mediating tumor immune escape (Xiong et al., 2022a). Lactylation frequently occurs in proteins involved in energy metabolism pathways, suggesting its significant role in biological systems.

Moreover, lactate elevates the lactylation level of PKM2, inhibits its tetramer-to-dimer transition, improves its activity, and decreases its nuclear distribution, primarily at the K62 site (Wang et al., 2022b). Lactate mediates the lactylation of PIK3C3/VPS34 at lysines 356 and 781 via the acyltransferase KAT5/TIP60. This modification enhances the binding of PIK3C3/VPS34 to BECN1, ATG14, and UVRAG, thereby increasing the activity of the PIK3C3/VPS34 lipid kinase and promoting the endolysosomal degradation pathway (Sun et al., 2023c). In macrophages, elevated histone lactylation regulates gene expression, including platelet-derived growth factor, platelet reactive protein (Thbs1), and the promoter-proximal region of VEGF (Cui et al., 2021).

Lactylation and nervous system disorders

Exogenous lactate administration in the CNS induces histone across various cell types, including neurons and glia. Neuronal excitation increases lactate levels through intracellular metabolic and glycolytic pathways, as well as lactate transport from astrocytes. This results in a dose-dependent increase in histone lactylation, proportional to neuronal activation levels (Hagihara et al., 2021).

Deleting Bach1 in microglia decreases the transcription of HK2 and GAPDH, leading to reduced lactate production and a significant decrease in H4K12la—a lactate-binding site in astrocytic progenitor cells. This reduction subsequently impairs the activation of the GP130-JAK/STAT3 pathway, affecting astrocyte function (Wang et al., 2024b). Histone H3 lysine 18 lactylation (H3K18la) increases in macrophages following LPS or bacterial stimulation, thereby influencing macrophage phenotypic changes. Exogenous lactate enhances histone lactylation and promotes the upregulation of Arg1 and Kif, which are critical for cellular responses (Irizarry-Caro et al., 2020). Additionally, Warburg effect-induced histone lactylation drives NF-κB-associated LINC 01127 expression, which consequently regulates MAP4K4 expression by directing POLR2A to its promoter. This JNK pathway activation promotes IkBα phosphorylation, improving glioma cell self-renewal via the MAP4K4/JNK/NF-κB axis, suggesting a potential novel treatment approach for glioma (Li et al., 2023). In a mouse glioblastoma model, oxamate decreases lactate production, reducing histone H3K18 lactylation. Furthermore, this downregulation affects CD39, CD73, and CCR8 gene promoter activities, altering the immunosuppressive tumor microenvironments and improving the immune activation of tumor-infiltrating CAR-T cells (Sun et al., 2023b).

Histone lactylation modifications also play critical roles in neurodegenerative diseases. For example, in AD, H4K12la increases in microglia near amyloid-beta (Aβ) plaques. This histone lactylation localizes to the promoters of glycolytic genes, thereby activating transcription and increasing glycolytic activity. This glycolysis/H4K12la/PKM2 positive feedback loop exacerbates microglial dysfunction in AD, suggesting PKM2 inhibition as a potential strategy to attenuate microglia activation and alleviate AD-associated cognitive decline (Pan et al., 2022b). In aging and AD mouse models, elevated lactate levels significantly increase H3K18la and Pan-Kla in microglia and hippocampal tissues. Increased H3K18la binds more readily to the promoters of Rela (p65) and NFκB1 (p50), leading to the upregulation of SASP components IL-6 and IL-8. This ultimately contributes to the development of pathological phenotypes linked to brain senescence and AD through the H3K18la/NF-κB axis (Wei et al., 2023). In the brains of mice treated with AlCl₃/D-gal, microglial overactivation directly correlates with cognitive decline. Nevertheless, physical exercise mitigates this overactivation and improves cognitive function. Intraperitoneal injections of sodium lactate (NaLa) produce similar effects, promoting a shift in microglial polarization from pro-inflammatory to a reparative phenotype (Han et al., 2023).

Lactate levels and histone lactylation modification levels are elevated in the spinal cord of CNS injury–related diseases. H4K12la lactylation significantly increases in microglial cells after SCI. Exogenous lactate further elevates H4K12la levels in these cells, promoting PD-1 transcription, microglia proliferation, axonal regeneration, and motor function recovery following SCI (Hu et al., 2024). This review focuses on investigating changes in lactate-mediated histone lactylation following SCI and explores its associated functional consequences. Additionally, targeted silencing of the astrocytic bromodomain-containing protein 4 (BRD4) gene in subarachnoid hemorrhage reduces H4K8la lactylation. This reduction exacerbates astrocyte A1 polarization, ultimately affecting neurological function recovery and prognosis in mice (Zhang et al., 2024a).

Although research on non-histone lactate modifications in the nervous system is limited, recent studies show that exercise-induced lactate generation significantly increases lactylation of synapse-associated protein 91 (SNAP91). This modification facilitates the formation of synaptic structures and neuronal activity in the medial prefrontal cortex, thereby enhancing tolerance to chronic restraint stress. These findings highlight the non-metabolic role of lactate in regulating neural function through exercise (Yan et al., 2024). In the peripheral nervous system, YY1 lactylation upregulates FGF2 expression in microglia, playing a crucial role in retinal neovascularization. This suggests that targeting the lactate/p300/YY1 lactylation/FGF2 axis offers a novel therapeutic approach for proliferative retinopathy (Wang et al., 2023b). Astrocytic LRP1 facilitates the transfer of mitochondria from astrocytes to neurons by inhibiting ARF1 lactylation and lactate production. Inhibiting LRP1 impairs mitochondrial translocation to damaged neurons, exacerbating ischemia-reperfusion injury in a stroke model and highlighting the critical role of astrocyte-neuron interactions in disease progression (Zhou et al., 2024a). What is the precise role of astrocyte-derived lactate-mediated lactylation in ischemic brain injury? Research shows that during the ischemic and hypoxic phase, diminished oxygen partial pressure reduces the oxidative capacity of the brain (Magistretti and Allaman, 2018). Although lactate accumulation is not a primary energy source, it promotes elevated protein lactylation modifications. However, under normal oxygen partial pressure conditions, lactate exerts neuroprotective effects. Further research shows that astrocyte-derived protein lactylation modifications exacerbate neuronal death and glial cell activation during ischemic and hypoxic conditions, contributing to increased ischemic brain injury (Xiong et al., 2024). Therefore, lactate acts as a double-edged sword in ischemic brain injury (Table 1).

Table 1.

Lactylation in the nervous system

Disease type	Model	Site of lactylation	Target	Result	Reference
	Mouse	H4K12la	LRRC15	Decreases activation of the GP130-JAK/STAT3 pathway, influencing the role of astrocytes	Wang et al., 2024b
		H3K18la		Promotes Arg1 and Kif upregulation, influencing macrophage phenotypic changes	Irizarry-Caro et al., 2020
Glioma	Human and mouse		LINC 01127	Improves glioma cell self-renewal via the MAP4K4/JNK/NF-κB axis	Li et al., 2023
Glioblastoma	Mouse	H3K18la		Modifies immunosuppressive TMEs and improves immune activation of tumor-infiltrating CAR-T cells	Sun et al., 2023b
AD	AD mouse	H4K12la	PKM2	Suppressing PKM2 could attenuate microglia activation, thus disrupting AD-associated learning and memory impairment	Pan et al., 2022b
AD	Aged mouse and AD mouse	H3K18la	Rela and NF-κB1	Upregulates SASP components IL-6 and IL-8 as well as promotes the development of pathological phenotypes of brain senescence as well as AD	Wei et al., 2023
SCI	Mouse	H4K12la	PD-1	Promotes microglia proliferation, axonal regeneration, and motor function recovery after SCI	Hu et al., 2024
SAH	Mouse	H4K12la	BRD4	Exacerbates astrocyte A1 polarization and ultimately affects the recovery of neurological function and prognosis in mice after SAH	Zhang et al., 2024a
	Mouse	SNAP91		Enhances tolerance to CRS by enhancing synaptic structure formation and neuronal activity in the mPFC	Yan et al., 2024
Proliferative retinopathy	Mouse	YY1	FGF2	Plays a vital role in retinal neovascularization	Wang et al., 2023b
Ischemic stroke	Mouse	LRP1	ARF1	Reduced mitochondrial translocation to damaged neurons exacerbates ischemia-reperfusion injury in an ischemic stroke model	Zhou et al., 2024a

AD: Alzheimer’s disease; CRS: chronic restraint stress; mPFC: medial prefrontal cortex; NF-κB: nuclear factor kappa B; PKM2: pyruvate kinase 2; SAH: subarachnoid hemorrhage; SCI: spinal cord injury; TMEs: tumor microenvironments.

The role of lactate as a pivotal link between histone lactylation and metabolic reprogramming in astrocytes remains unclear. Additionally, the specific roles and interactions between lactate and lactylation within astrocytes remain underexplored. Current literature offers limited insights into these mechanisms, highlighting the need for future investigation, which will guide future studies.

Relationship between lactylation and N6-methyladenosine

In eukaryotes, m6A methylation is the most prevalent mRNA modification, regulating multiple stages of the RNA lifecycle, including transcription, maturation, translation, degradation, and stability (An and Duan, 2022). Most methylation sites occur near the 3′ untranslated region, coding region, and terminator (Huang et al., 2020b). The m6A modification is a dynamic and reversible process. It is added by m6A methyltransferases (e.g., METTL3, METTL14, WTAP) and removed by demethylases (e.g., FTO, ALKBH5). Furthermore, m6A-binding proteins (e.g., YTHDF1, YTHDF2) specifically recognize and bind to the m6A modification, which is complementary to each other to maintain their dynamic stability and influence the fate of the mRNA (Shi et al., 2019; Wang et al., 2020). Lactylation is closely linked to m6A methylation. Histone lactylation influences disease progression by regulating the expression of m6A methylases, demethylases, and reader proteins. Extensive research supports the role of histone lactylation in regulating m6A modifications or vice versa regarding tumorigenesis and other lung diseases (Mei et al., 2024; Wang et al., 2024a; Wu et al., 2024).

Research on targeting histone lactate-regulated m6A modifications in the nervous system remains limited. Studies show that lactate produced from glycolysis enhances H3K18la lactylation, which subsequently increases YTHDF2 transcription. This process degrades key proteins, such as TP53 and PER1, via m6A sites, promoting melanoma progression (Yu et al., 2021). In diabetic retinopathy, lactate-mediated histone lactylation upregulates the expression of the demethylase FTO. FTO subsequently modulates the stability of CDK2 mRNA via the m6A/YTHDF2 axis, thereby promoting endothelial cell cycle progression and tip cell formation. Endothelial-microglia interactions contribute to retinal inflammation and neurodegeneration. Targeting FTO offers a promising therapeutic approach to mitigate diabetic retinopathy progression (Chen et al., 2024).

The m6A-reading protein IGF2BP2 regulates the stability of Aldolase A through m6A modification in hepatic stellate cells. This regulation influences its expression, leading to increased lactate production, which serves as a substrate for lactylation and modulates hepatic stellate cell activation and liver fibrosis (Zhou et al., 2024b). However, studies on m6A-mediated lactylation modifications in the nervous system remain lacking, consequently offering new directions for future studies. Does the close link between the target m6A and lactylation offer therapeutic potential for neurological disorders?

Therefore, an in-depth investigation of the crosstalk between histone lactylation and m6A modifications in neurological disorders is essential for identifying targets to develop drugs for these conditions. Moreover, researchers should explore m6A modification sites on key glycolytic enzymes and histone lactylation sites on methylases, demethylases, and reading proteins, to provide novel insights regarding the roles of lactate (Figure 4).

Figure 4.

Epigenetically mediated metabolic reprogramming.

M6A dynamically modulates mRNA through a complex interaction of methyltransferase (‘writer’) activity, recognition by ‘reader’ proteins, and demethylation by demethylase (‘eraser’) enzymes. This regulation affects the expression and stability of mRNAs encoding key glycolytic enzymes, including HK2, PFK, and PKM2. The increased activity of these enzymes improves lactate production, which is crucial for mediating axonal regeneration, neuronal synaptic plasticity, and inflammatory responses in the CNS. Increased lactate production also improves lactylation levels, establishing a direct link with m6A modification. Moreover, lactate is intricately linked to other post-translational modifications, such as acetylation and ubiquitination, highlighting its wide regulatory effect on cellular functions. Created with BioRender.com. CNS: Central nervous system; HK2: hexokinase 2; m6A: N6-methyladenosine; PFK: phosphofructokinase; PKM2: pyruvate kinase.

Relationship between lactate and ubiquitination

Ubiquitination modifications primarily target proteins for degradation by the proteasome, regulating their degradation, localization, metabolism, and function (Popovic et al., 2014). Ubiquitination involves a cascade of three active enzymes: E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; and E3, ubiquitin-protein ligase. Ubiquitination initiates with the transfer of ubiquitin from the ubiquitin-activating enzyme (E1) to a ubiquitin-conjugating enzyme (E2), forming a covalently linked intermediate (E2-Ub) (Pao et al., 2018). Ubiquitination modification is a reversible process. Deubiquitinating enzymes remove ubiquitin molecules, thereby restoring protein structure and function (Liao et al., 2022). This regulation maintains neuronal homeostasis and neural signaling within the nervous system (Jung et al., 2023; Sun et al., 2023a).

In the nervous system, lactate regulates ubiquitination modifications indirectly. For example, in astrocytes, reduced activity of the anaphase-promoting complex/cyclosome (APC/C)-Cdh1 ubiquitin ligase leads to increased PFKFB3 stabilization. This process enhances glycolysis and lactate release, which neurons utilize as a redox substrate for energy production. Thus, APC/C-Cdh1 coordinates energy metabolism coupling between astrocytes and neurons (Almeida et al., 2023). Other studies show that lactate elevation upregulates the intracellular expression of NDRG2 in astrocytes and inhibits its ubiquitination under glucose-oxygen deprivation/reoxygenation conditions. In contrast, lower levels of NDRG2 trigger an inflammatory response characterized by c-jun phosphorylation, a protein involved in cell signaling, which ultimately upregulates TNF-α expression. These elevated TNF-α levels disrupt the normal balance of the local microenvironment (Xu et al., 2022). The literature shows that lactylation modifies K91 through the covalent binding of lactic acid molecules to TFEB. This modification prevents TFEB from interacting with the EZ ubiquitin ligase WWP2, inhibiting its ubiquitination and proteasomal degradation. Consequently, this process facilitates the expression of autophagy-related genes and lysosome-related functions, playing a crucial role in maintaining cellular homeostasis (Huang et al., 2024).

Ubiquitination modifications also influence lactate production in the nervous system. For example, a study found that circSRRM4 binds to SRSF3 in epilepsy, preventing its entry into the ubiquitin-proteasome pathway. SRSF3 interacts with PKM pre-mRNA, mediating selective splicing and subsequently upregulating the expression of PKM2. Increased PKM2 expression promotes glycolysis and lactate production, providing the energy required to sustain seizure activity. Therefore, selective silencing of circSRRM4 decreases the incidence and frequency of epilepsy and prevents neuronal loss, suggesting it is a potential therapeutic target for epilepsy prevention and treatment (Zhao et al., 2023). Overall, lactate and ubiquitination modifications share an interconnected relationship.

Relationship between lactate and acetylation

Histone acetylation regulates gene expression by modifying the charge state of histones, which affects the interaction between DNA and proteins (Shvedunova and Akhtar, 2022). Acetylation plays a critical role in neurological disorders, such as synaptic plasticity, axonal transport, and neuronal differentiation, through the co-regulation of histone acetylases and deacetylases (Chamberlain et al., 2021; Li et al., 2021; Bergamasco et al., 2024). In the nervous system, histone acetylation primarily depends on the metabolite acetyl coenzyme A (Mews et al., 2019).

Lactate indirectly regulates histone acetylation, e.g., by modulating the activity of acetyltransferases and deacetylases or altering chromatin structure and gene transcriptional activity, affecting acetylation levels. Lactate modulates the H3K27ac enhancer landscape, promoting enhancer-dependent transcription of the Nr4a1 gene via H3K27 acetylation. This leads to the upregulation of lactate-specific gene programs. Lactate significantly reduces the binding sites for AP-1 on interferon regulatory factor, NF-κB, and the transcription factors IL-6 and Ptgs2 in the DNA regions, transcriptionally inhibiting macrophage pro-inflammatory functions. This study shows a crucial mechanism of lactate-mediated epigenetic modifications in the macrophage microenvironment (Shi et al., 2024). The overexpression of the pyruvate dehydrogenase β-subunit, a key enzyme linking glycolysis to the TCA cycle, enhances H3K9 acetylation and alters the expression of Rsa-14-44 and Pla2g4a. These genes influence key processes, including the breakdown of arachidonic acid and activation of the Ras signaling pathway, which promotes axon regeneration. Blocking MCT2, which modulates lactate uptake, counteracts this regenerative effect. This finding suggests that PDHB promotes axon regeneration by leveraging the energy derived from lactate (Jiang et al., 2023). Studies show that the metabolic shift from aerobic glycolysis to oxidative phosphorylation serves as a crucial marker of neuronal differentiation (Zheng et al., 2016). TP53-inducible glycolysis and apoptosis regulator (TIGAR) serves as an endogenous inhibitor of glycolysis and it is overexpressed in mature neurons. TIGAR inhibits lactate production while enhancing oxygen consumption and ATP production in differentiated NSCs. TIGAR knockdown inhibits acetyl coenzyme A and H3K9 acetylation levels at the promoters of Ngn1, Neurod1, and GFAP. Conversely, acetate, a precursor of acetyl coenzyme A, accelerates H3K9 acetylation and reverses the effects of TIGAR deficiency on NSC differentiation. The activation of the lactate-histone acetylation axis enhances neuronal differentiation (Zhou et al., 2019). In pathological retinal angiogenesis, glycolysis in macrophage/microglia generates significant amounts of acetyl coenzyme A. This accumulation leads to histone acetylation and activates PRAGM-CSF-related genes, thereby upregulating M1 and M2 markers and promoting the production of pro-inflammatory and pro-angiogenic cytokines. Glycolytic metabolites play a critical role in the retinal angiogenic microenvironment by reprogramming macrophages/microglia towards an angiogenic phenotype, establishing a reciprocal activation loop with these immune cells and endothelial cells (EC). Lactate, the end product of glycolysis, potentially regulates the expression and accumulation of acetyl-CoA and histone acetylation modifications through metabolic pathways. This novel understanding of the interplay between macrophages/microglia, ECs, and metabolites offers promising opportunities for therapeutic interventions in pathological retinal angiogenesis (Liu et al., 2020).

Can histone acetylation modifications regulate lactate production? The PDK-lactate axis is crucial in the development and progression of CNS disorders owing to its role in metabolic reprogramming, making it a subject of significant interest. Acetyl-CoA-induced acetylation of histone H3K9 in primary neurons and Neuro-2a cells under high-glucose conditions enhances PDK1 expression, thereby promoting lactate production. PDK1 upregulation inhibits the high glucose-induced ROS production and neuronal apoptosis, suggesting a potential role in alleviating memory loss (Yao et al., 2023).

These findings suggest an inextricable relationship between lactate and histone acetylation, where lactate modulates histone acetylation levels and histone acetylation indirectly regulates lactate production. However, future studies should explore the close relationship between other epigenetic modifications and acetylation.

Relationship between lactate and phosphorylation

Phosphorylation is a fundamental, pervasive, and essential mechanism for regulating protein activity and function. Phosphorylation mainly occurs on two classes of amino acids: serine (including threonine) and tyrosine. Phosphorylation activates or inhibits proteins, allowing them to participate in the regulation of various signaling pathways (Huang et al., 2020a; Bilbrough et al., 2022). It also regulates gene transcriptional activity by affecting the structure and stability of chromatin. Phosphorylation modifications are strongly linked to neurodegenerative and psychiatric diseases, among others (Yang et al., 2019a, b; Pérez-Núñez et al., 2023).

However, can lactate directly or indirectly modulate phosphorylation modifications? Could it regulate phosphorylation in the nervous system? Literature shows that spinal astrocyte activation produces lactate, which contributes to the expression of neuropathic pain. Further studies show that intrathecal injection of lactate significantly upregulates c-Fos and cofilin phosphorylation, while α-cyano-4-hydroxycinnamate attenuates this effect. This reveals that activated astrocytes maintain mechanical nociceptive sensitization by supplying excess lactate in neuropathic pain (Miyamoto et al., 2019).

Future studies should investigate how lactate, as a modulator of phosphorylation modifications, influences disease progression in the nervous system. Understanding how other epigenetic modifications mediate phosphorylation in the nervous system remains a research question. Their dynamic regulation warrants active inquiry and consideration.

Treatment Strategies Targeting Astrocyte Lactate Metabolic Programming

Several drugs and targets regulate the metabolic reprogramming of lactate in astrocytes. These drugs are employed in various nervous system disease treatments to alter energy homeostasis and participate in signal transduction processes. They consequently affect the progression of various diseases, such as epilepsy, Parkinson’s disease (PD), AD, ischemic encephalopathy, fear memory, and TBI (Table 2).

Table 2.

Treatment strategies targeting lactate metabolic programming in astrocytes

Disease type	Treatment	Model	Result	Reference
Epilepsy	CircRNA SRRM4	Rats with kainic acid-induced epilepsy, human epileptic brain tissue	Promotes glycolysis and reduces neuronal loss.	Zhao et al., 2023
PD	Ganglioside GM1	Primary mouse cortical astrocyte-neuron co-cultures	Enhancement of glucose uptake in astrocytes, mobilization of glycogen stores, and secretion of lactate for neuroprotection.	Finsterwald et al., 2021
	Octopamine	Orai1fl/fl, GFAP-Cre mice	Promotes lactate secretion and prevents neurodegeneration.	Shum et al., 2023
AD	FGF21	APP/PS1 transgenic AD mice model	FGF21 exerts neuroprotection by regulating ANLS	Sun et al., 2020
	Metformin	Sub-chronic aluminum exposure mouse model	Relieves imbalances in glucose metabolism and increases the number of neurons.	Song et al., 2022
	Osteocalcin	APP/PS1 transgenic AD mice model	Facilitates the clearance of Aβ promotes lactate production.	Shan et al., 2023
	Sodium butyrate	Aβ25–35-injected AD mouse model	Promotes ANLS and increases neuronal cell activity.	Wang et al., 2022a
	GLP-1	4-month-old 5×FAD mice, an astrocytic model of AD by treating primary astrocytes with Aβ1–42	Promotes glycolysis, neuronal survival, and axonal growth	Zheng et al., 2021
Ischemic encephalopathy	Selenium Nanoparticles	Astroglial cell cultures were isolated from the brains of 1–2-day-old rats	Inhibition of apoptosis and expression of pro-inflammatory factors and promotion of lactate release.	Varlamova et al., 2021
	Mir-210	Isolate human astrocytes surrounding stroke lesions	Promotes glycolysis and inhibits inflammation.	Kieran et al., 2022
Fear memory	PACAP	The generation of PACAP (−/−) mice by gene targeting	Induction of lactate production and secretion.	Kambe et al., 2021
TBI	EPO	Neuron-conditioned astrocytes in primary culture	Promotes lactic acid production and exerts neuroprotective effects	Blixt et al., 2023

AD: Alzheimer’s disease; Aβ: amyloid-β; ANLS: astrocyte-neuronal lactate shuttle; EPO: erythropoietin; FGF21: fibroblast growth factor 21; PACAP: pituitary adenylate cyclaseactivating polypeptide; PD: Parkinson’s disease; TBI: traumatic brain injury.

However, despite these advances in basic research, predominantly in animal models, preclinical and clinical applications are ongoing. Current clinical research on lactate primarily focuses on the diagnosis, prediction, and assessment of TBI (Bouzat et al., 2014; Bernini et al., 2022; Martin-Rodriguez et al., 2024). For example, an elevated brain lactate/pyruvate ratio after TBI reflects impaired energy metabolism. Administration of disodium 2,3-13C2 succinate via retrograde dialysis into 33 monitored brain regions in patients shows that succinate administration decreases the brain lactate/pyruvate ratio and improves energy metabolism (Khellaf et al., 2022). However, lactate is used to improve reperfusion after TBI (Carteron et al., 2018).

However, strong literature support for the use of lactate in other neurological disorders is lacking. Therefore, future research is necessary to determine its clinical applications for the diagnosis, treatment, and evaluation of these conditions. The mode of drug delivery targeting astrocyte metabolic reprogramming and the ability of these drugs to cross the blood–brain barrier are important areas for investigation (Han and Jiang, 2021). Additionally, does lactate play different roles in various disease models?

Parkinson’s disease

GM1 is expressed on the plasma membrane of most vertebrate cells and recognized for its neuroprotective effects against various CNS disorders, such as, SCI, PD, and Huntington’s disease. It enhances glucose uptake, mobilizes glycogen stores, and promotes lactate secretion in astrocytes by increasing the expression of various metabolic enzymes, such as PTG, HK, Na⁺/K⁺ ATPase subunit α2, and pyruvate dehydrogenase. Therefore, exploring the molecular mechanisms underlying GM1-mediated astrocyte glycolysis and developing effective gangliosides for treating metabolically impaired CNS diseases is essential (Finsterwald et al., 2021).

In PD, the protein alpha-synuclein can induce an abnormal rise in octopamine levels. This increase disrupts critical communication channels between astrocytes and neurons by inhibiting lactate production in astrocytes. Under normal conditions, octopamine activates a signaling pathway in astrocytes involving Orai1, Ca²⁺, and calmodulin-dependent phosphatase, ultimately stimulating lactate secretion. This lactate is subsequently imported into neurons via MCT2, alleviating α-synuclein-induced ATP deficiency and inhibiting neurodegeneration. Elucidating the protective effects of octopamine against toxic astrocyte phenotypes may enhance lactate production, potentially alleviating PD. The FDA-approved drug FK506 exhibits modulatory effects by partially inhibiting calmodulin phosphatase (Shum et al., 2023).

Alzheimer’s disease

Astrocyte metabolic reprogramming plays a critical role in AD. Chronic aluminium exposure inhibits glucose uptake, disrupts the ANLS, and suppresses glucose metabolism via the HIF-1α/PDK1/PDH pathway, thereby promoting glycolysis and resulting in morphological damage and neuronal loss in the cerebral cortex. Metformin downregulates HIF-1α and PDK1 expression levels, decreases HK activity, and enhances ATP levels. Therefore, metformin can suppress HIF-1α levels, alleviates glucose metabolism imbalance, and increases neuronal count, suggesting that metformin can inhibit cognitive dysfunction caused by chronic aluminium exposure (Song et al., 2022).

In AD, osteocalcin, an osteoblast-derived protein, modulates brain function. This bone-derived hormone stimulates glucose uptake by astrocytes into the hippocampus. Increased glucose consumption elevates lactate production and astrocyte proliferation. This alleviates anxiety-like behavior and cognitive dysfunction in mice models of AD while reducing Aβ deposition by enhancing its clearance (Shan et al., 2023). Sodium butyrate promotes ANLS and neuronal activity, maintaining energy metabolism homeostasis in the CNS and ameliorating cognitive deficits in AD mice (Wang et al., 2022a).

Ischemic encephalopathy

During ischemic encephalopathy, selenium nanoparticles appear to selectively target astrocytes across different brain regions. These nanoparticles activate an IP3 receptor signaling pathway, triggering the release of calcium ions from the endoplasmic reticulum within the astrocytes. This generates calcium signals that open connexin Cx43 hemichannels, facilitating the secretion of ATP and lactic acid into the extracellular matrix. These actions inhibit apoptotic and pro-inflammatory gene expression while suppressing hyperexcitability in the neuronal network, thereby providing neuroprotection (Varlamova et al., 2021). In ischemic stroke lesions, elevated miR-210 expression enhances astrocyte glycolytic activity, accelerates lactate production, and upregulates the expression of anti-inflammatory molecules, all of which promote neuronal survival following a stroke (Kieran et al., 2022).

Fear memory

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous molecule that regulates fear memory processes by inducing astrocytes to produce and secrete lactate via the PAC1 receptor. Targeting astrocyte lactate secretion with PACAP receptor antagonists represents a potential therapeutic strategy for disorders like PTSD. However, substantial research is required to evaluate the efficacy and safety of this approach in clinical settings (Kambe et al., 2021).

Traumatic brain injury

Although clinical and preclinical applications for lactate in TBI exist, the basic research on its mechanisms and translational potential remains challenging. Previously, we found that erythropoietin (EPO) increases Na⁺, K⁺-ATPase-dependent glutamate uptake, restores intracellular acidification, and enhances lactate release. Moreover, EPO boosts NADH production in both astrocytes and neurons. Therefore, EPO regulates the metabolic reprogramming of astrocytes, conferring neuroprotective effects in cerebral ischemia following TBI (Blixt et al., 2023). Therefore, future studies in basic research should clarify the exact role of lactate in TBI.

Limitation

This review focused exclusively on the beneficial effects of lactate as an energy substrate and signaling molecule. However, acknowledging that lactate could also have detrimental consequences in certain neurological disorders is crucial. In patients with panic disorder, intravenous lactate infusion regularly induces panic attacks due to a reduction in dopaminergic activity (Lingjaerde, 1985). Lactate appears to be a stronger stimulus for panic attacks than CO₂ (Tural and Iosifescu, 2022). Additionally, the role of lactate as a therapeutic agent in ischemic brain injury remains complex, exerting beneficial and detrimental effects on disease progression. This complexity warrants a more comprehensive evaluation of the underlying mechanisms involved. The potential of lactate for clinical applications in neurological disorders beyond TBI should be explored.

Although lactate-mediated sumo modification and DNA methylation are currently being investigated in other areas of research (Maiuri et al., 2018; Liu et al., 2023), strong literature supporting these connections in neurological disorders remains lacking. Therefore, future research should explore the relationship between lactate, sumo modification, and DNA methylation in these disorders.

Conclusion and Future Perspective

Lactate plays dual roles in the CNS, acting as an energy source from astrocytes and a signaling molecule that critically influences metabolic adaptation in these cells. Lactate is a key mediator that modulates astrocyte-neuron shuttling. Given the specific effect of lactate in various CNS diseases and cells, further investigation is necessary to explore lactate production and metabolic reprogramming in astrocytes to improve the progression of CNS diseases. Lactate acts as a link between epigenetic modifications and metabolic reprogramming. Understanding the precise mechanisms through which astrocytes reprogram their metabolism and how epigenetics influences these processes holds significant promise for developing new treatments for CNS diseases.

Studies also show a strong link between CNS diseases and astrocyte metabolic reprogramming (Figure 5). Drugs targeting astrocyte metabolic reprogramming could effectively prevent the progression of CNS diseases. Thus, further studies are warranted to investigate the link between epigenetic modifications and metabolic reprogramming.

Figure 5.

Schematic illustration of lactate-mediated metabolic reprogramming in astrocytes.

Created with BioRender.com.

Funding Statement

Funding: This work was supported by the National Natural Science Foundation of China, Nos. 82071383, 82371392 (to BN); the Natural Science Foundation of Shandong Province of China (Key Project), No. ZR2020KH007 (to BN); “Taishan Scholar Distinguished Expert Program” of Shandong Province, No. tstp20231257 (to BN); Health Commission Science and Technology Plan Project of Jinan, No.2023-1-8 (to YZ).

Data availability statement:

Not applicable.