Under physiological conditions, glucose undergoes glycolysis in the cytoplasm of normal cells (Fig. 1), yielding two molecules of pyruvate along with a small amount of ATP and NADH. Depending on oxygen availability, pyruvate enters the mitochondria under aerobic conditions for complete oxidation via the tricarboxylic acid (TCA) cycle, where it produces CO₂, H₂O, NADH and FADH2 to fuel oxidative phosphorylation (OXPHOS). Under anaerobic conditions, pyruvate is instead reduced to lactate, regenerating NAD⁺ to sustain glycolysis.

In healthy cells, glycolysis and mitochondrial respiration operate synergistically, enabling the complete oxidation of glucose and the production of up to 38 ATP molecules, ensuring sufficient energy for cellular functions. However, cancer cells exhibit a distinct metabolic preference known as the Warburg effect, whereby they rely heavily on aerobic glycolysis even in the presence of oxygen (9). This less efficient pathway generates only two ATP molecules per glucose molecule, with lactate as the major end product. Several factors contribute to this metabolic shift in cancer cells (Fig. 2): i) Tumor cells have a high demand for energy that relies more on efficient glycolysis than on the TCA cycle and OXPHOS (9). ii) Intracellular regulatory mechanisms: Compared with normal cells, cancer cells have a lower dependence on OXPHOS, which helps to avoid the inhibition of glycolytic pathways by ATP, citrate and reactive oxygen species (ROS) (10). Additionally, a reduction in ROS production can decrease cytotoxicity and improve survival rates (11). Furthermore, lactate production helps convert NADH to NAD⁺, thus preventing the depletion of NAD⁺, which could lead to cell death (12). iii) Importance of intermediates: The intermediates of glycolysis can serve as precursors for the synthesis of amino acids, nucleotides, fatty acids and glycogen, promoting the growth of tumor cells (9). iv) Impact of the tumor microenvironment (TME): The hypoxic conditions present in the TME enhance glycolysis while inhibiting the activity of OXPHOS (13). Moreover, lactate, the final product of glycolysis, acts as a signaling molecule, helping shape the TME and enhancing the adaptability of cancer cells under hypoxic conditions. The enzyme LDH serves a central role in the reversible conversion of pyruvate to lactate while maintaining the NAD⁺/NADH redox balance. LDH exists as five tetrameric isoenzymes, LDH1-LDH5, which are composed of varying combinations of two subunits, LDHA and LDHB. These isoenzymes exhibit distinct tissue distributions and functional roles (14,15). Notably, LDHA (also known as LDH-M) predominantly catalyzes the conversion of pyruvate to lactate and is frequently upregulated in cancer cells with high glycolytic activity, thereby promoting the Warburg effect and contributing to malignant progression (16).

As aforementioned, tumor cells predominantly generate large amounts of lactate through aerobic glycolysis. The accumulation of intracellular lactate can lead to acidification of the cytosol, necessitating timely and efficient export of lactate to maintain the intracellular pH balance and metabolic homeostasis. The transport of lactate across the plasma membrane is primarily mediated by MCTs, a family of transmembrane proteins that specifically facilitate the proton-coupled transport of monocarboxylates such as lactate and pyruvate (17). In this mechanism, lactate forms a complex with protons and is transported out of the cell via MCTs (18). Initially, MCTs were considered merely passive channels for metabolic waste disposal; however, increasing evidence has suggested that MCTs serve crucial roles in shaping the TME and facilitating immune evasion (19,20). Among them, MCT1 and MCT4 are key isoforms involved in lactate transport, and are frequently upregulated in breast cancer, colorectal cancer (CRC), lung cancer and glioma (21).

The expression of these genes is closely associated with increased glycolytic activity, and enhanced potential for cell migration and invasion. MCT1 is broadly expressed in both normal and tumor tissues, with high affinity for both lactate and pyruvate, and is involved primarily in lactate uptake (22,23). By contrast, MCT4 is highly expressed in glycolytic tumor cells, has a relatively high affinity for lactate (24) and mainly mediates lactate efflux (25,26). The expression and activity of MCTs are regulated by multiple mechanisms. Hypoxia, a hallmark of solid tumors, activates hypoxia-inducible factor-1 (HIF-1), which transcriptionally upregulates MCT4 and other lactate transport-related genes. Additionally, signaling pathways such as p53 can influence lactate transport by modulating the expression and function of MCTs (21). Intracellular factors such as pH (27) and calcium concentration (28) also contribute to the fine-tuning of MCT activity.

In summary, through MCT-mediated lactate transport, tumor cells efficiently export excessive lactate to adapt to their metabolic demands and microenvironmental challenges. This process supports sustained tumor growth and progression, highlighting the potential of MCTs as therapeutic targets in cancer metabolism.

DNA methylation is a pivotal epigenetic modification involving the covalent addition of a methyl group to a DNA molecule, which is typically catalyzed by DNA methyltransferases (DNMTs) (29-31). This process commonly occurs at cytosine residues within CpG dinucleotides, particularly within CpG islands (32). Under the catalytic activity of DNMTs, a methyl group from S-adenosylmethionine is transferred to cytosine, forming 5-methylcytosine (5-mC). Although DNA methylation does not alter the DNA sequence, it serves a crucial role in regulating gene expression and maintaining cellular identity (33).

In cancer biology, aberrant DNA methylation is closely associated with tumor initiation, progression and metastasis. Notably, research has highlighted its role in modulating lactate metabolism in tumors, a hallmark of cancer metabolism (34). By regulating genes involved in glycolysis, lactate production, transport and utilization, DNA methylation contributes to the metabolic reprogramming of tumor cells and shapes the TME, ultimately influencing tumor growth, survival and immune escape. To meet the high energy demands of rapid proliferation, tumor cells preferentially utilize aerobic glycolysis, or the Warburg effect, which leads to excessive lactate production (35). DNA methylation acts as a key regulator in this metabolic shift. It alters the expression of critical metabolic enzymes such as hexokinase 2 (HK2) (36) and LDHA, as well as signaling molecules, thereby reshaping tumor metabolic phenotypes. For example, hypermethylation of the HK2 promoter has been shown to suppress its transcription, reducing glycolytic flux and lactate production, and ultimately impeding CRC progression (37). In ovarian cancer, DNMT3A-mediated methylation of the microRNA (miRNA/miR)-603 promoter silences miR-603, which normally suppresses HK2. The resulting upregulation of HK2 promotes glucose uptake and lactate generation, enhancing tumor cell growth and invasion (38). Similarly, in isocitrate dehydrogenase (IDH)-mutant glioma, hypermethylation of the LDHA promoter inhibits transcription factor binding, downregulates LDHA expression (39) and reduces lactate production, impairing glycolytic capacity and tumor growth (40).

Lactate transport across the cell membrane is essential for maintaining metabolic homeostasis and promoting cancer progression. DNA methylation also regulates this process by modulating the expression of MCTs (41). In renal cancer, methylation of the SLC16A3 promoter reduces MCT4 expression, hindering lactate export and leading to intracellular lactate accumulation and microenvironmental alterations (42). Conversely, the inhibition of DNMTs with agents such as 5-azacytidine can induce methylation at the MCT1 promoter, downregulating its expression and impairing lactate uptake, which inhibits tumor cell survival (43). Notably, some enzymes, such as histone-lysine (K) N-methyltransferase SETDB (SETDB1), promote MCT1 expression via histone H3K9 trimethylation, increasing lactate uptake and activating oncogenic pathways, such as the PI3K/AKT and MAPK pathways, to support cancer progression (41). Moreover, DNA methylation influences upstream regulators of glucose metabolism. In esophageal squamous cell carcinoma, DNMT1-mediated hypermethylation of the RAR related orphan receptor A (RORA) promoter suppresses RORA expression, reducing its inhibitory effect on SLC2A3 [a glucose transporter (GLUT)], thereby increasing glucose uptake and glycolytic activity, leading to lactate accumulation and tumor progression (44).

Intracellular lactate metabolism is tightly regulated by enzymes such as LDHB. In breast cancer, frequent methylation of the LDHB promoter silences its expression, disrupting lactate-to-pyruvate conversion, leading to lactate accumulation that supports tumor growth and immune evasion (45). Similarly, in hepatocellular carcinoma (HCC), LDHB promoter methylation suppresses lactate clearance, exacerbating acidosis in the TME, and promoting proliferation and metastasis while inhibiting immune cell function (46). Additionally, in melanoma, hypomethylation of the transketolase-like-1 promoter enhances its expression, linking the pentose phosphate pathway to glycolysis, and increasing aerobic glycolysis and lactate production, thereby supporting immune escape and tumor progression (47). Notably, epigenetic regulation does not act in isolation. Transcription factors such as HIF-1α are central to lactate metabolism and simultaneously regulate glycolytic gene expression, MCT expression and mitochondrial function (48). For example, in oral squamous cell carcinoma, ASC stabilizes HIF-1α, which in turn enhances the transcription of glycolysis-related genes (49). In hypoxic pancreatic tumors, HIF-1α activation further drives glycolytic reprogramming by binding to hypoxia response elements (50). DNA methylation serves as a pivotal epigenetic mechanism that drives the tumor glycolytic phenotype through three core pathways in coordination with HIF-1α: i) Silencing negative regulators of HIF-1α via hypermethylation, enabling sustained HIF-1α activation to establish the foundation for metabolic reprogramming (51); ii) activating HIF-1α downstream glycolytic genes through hypomethylation, enhancing glucose uptake and lactate fermentation; and iii) suppressing mitochondrial aerobic respiration genes via hypermethylation, epigenetically obstructing OXPHOS and redirecting metabolic flux toward glycolysis (52).

In summary, DNA methylation is a key epigenetic mechanism that regulates various aspects of lactate metabolism in cancer, including glycolysis, lactate transport and downstream metabolic pathways. By influencing genes such as HK2, LDHA, LDHB, MCT1 and MCT4, as well as modulators such as HIF-1α, DNA methylation reshapes tumor metabolism and contributes to immune suppression, microenvironmental changes and tumor aggressiveness. Understanding these mechanisms may pave the way for novel therapeutic strategies targeting epigenetic and metabolic vulnerabilities in cancer.

RNA methylation, accounting for >60% of all RNA modifications, has emerged as a crucial mechanism in the epitranscriptomic regulation of gene expression (53). The major RNA methylation types include N6-methyladenosine (m6A), N1-methyladenosine, 2′-O-dimethyladenosine, 7-methylguanine (m7G) and 5-mC (Table I) (54). Among these, m6A is the most abundant and functionally diverse modification and is enriched near stop codons, 3′ untranslated regions (3′UTRs), and both intronic and exonic regions of precursor and mature mRNAs. It serves key roles in mRNA decay, splicing and translation (55). RNA methylation (Fig. 3) is dynamically regulated by three groups of proteins: Methyltransferases ['writers', such as methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3), methyltransferase 1, transfer (t)RNA methylguanosine (METTL1) and N-actetyltransferase 10 (NAT10)], binding proteins ['readers', such as insulin-like growth factor 2 mRNA-binding protein (IGF2BP)1, IGF2BP3 and YTH m6A RNA binding protein C1 (YTHDC1)] and demethylases ['erasers', such as fat mass and obesity-associated protein and AlkB homolog 5, RNA demethylase (ALKBH5)]. These factors collectively orchestrate the methylation landscape, thereby influencing the processing, localization, translation (56) and stability of various RNA species, including mRNAs, tRNAs and long ncRNAs (lncRNAs) (57).

Studies have revealed that dysregulated RNA methylation is closely associated with tumorigenesis and progression in a wide range of cancers, including HCC, CRC, gastric cancer, lung cancer and prostate cancer, underscoring its potential value in cancer diagnosis and therapy (58-60). RNA methylation modulates lactate metabolism primarily by influencing the stability, splicing or translational efficiency of key glycolytic enzymes. For example, lactate, which is primarily generated by LDHA, can be regulated at multiple levels via RNA modifications. In lung adenocarcinoma (LUAD), lactate uptake via MCT1 induces K lactylation (Kla) of RNA binding motif protein 15 (RBM15) at K850, which prevents RBM15 degradation and enhances m6A methylation. This stabilizes LDHA mRNA and promotes lactate production, forming a lactate-RBM15-m6A-LDHA positive-feedback loop that promotes cancer progression via sustained metabolic and epigenetic signaling (61).

Additionally, NAT10-mediated N4-acetylcytidine acetylation stabilizes YTHDC1 mRNA, which in turn promotes the expression of glycolytic enzymes such as LDHA and phosphofructokinase (PFK)M, increasing glucose uptake and lactate production in osteosarcoma (62). In triple-negative breast cancer, the METTL3/IGF2BP1 axis stabilizes protein arginine methyltransferase 7 mRNA through an m6A-dependent mechanism, activating the WNT/β-catenin pathway and specifically enhancing glycolytic activity (63). Similarly, METTL1-mediated m7G modification promotes pyruvate kinase isozymes M1/M2 (PKM2) expression in CRC, forming a METTL1/PKM2/H3K9la loop that not only drives lactate production but also facilitates histone lactylation, thereby integrating metabolic changes with transcriptional regulation (64).

Moreover, increased lactate export acidifies the TME, which further activates METTL3 and perpetuates a pro-tumorigenic feedback loop (61). On the other hand, demethylases can reverse RNA methylation and inhibit lactate metabolism. For example, IL-37 suppresses ALKBH5 expression, increasing m6A methylation of Wnt5B mRNA and downregulating its expression. Concurrently, IL-37 reduces the expression of the glycolytic enzyme PFKFB3, leading to decreased glucose uptake and lactate production, thereby impeding LUAD progression (65). Reader proteins further contribute to lactate metabolism by selectively recognizing methylated RNAs. In lung squamous cell carcinoma, IGF2BP3 binds to m6A-modified CCCTC-binding factor (CTCF) mRNA and activates the IGF2BP3/CTCF/5′-nucleotidase domain containing 2 (NT5DC2) axis, which enhances glycolysis through the upregulation of NT5DC2 (66). In CRC, IGF2BP2 binds to the m6A-modified lncRNA ZFAS1 and activates the ATPase activity of Obg like ATPase 1 (OLA1), forming a metabolism-epigenetics regulatory network that drives the Warburg effect (66).

Overall, RNA methylation serves as a multilayered and multidimensional regulator of lactate metabolism in tumors. Multiple positive feedback loops between RNA methylation and lactate production reinforce metabolic adaptation and tumor growth. The involvement of readers and erasers further adds dynamic complexity to this regulatory network. These findings highlight the critical role of RNA modifications in tumor metabolic reprogramming and suggest novel therapeutic opportunities for targeting the epitranscriptome in cancer.

In eukaryotic cells, genetic information is stored in a highly organized chromatin structure. The fundamental unit of chromatin, the nucleosome, consists of DNA wrapped around histone octamers composed of H2A, H2B, H3 and H4 (67). PTMs, such as methylation, occur on the N-terminal tails and globular domains of histones, modulating gene expression and DNA repair by altering chromatin structure or recruiting transcriptional regulators (68). Histone methylation is dynamically regulated by methyltransferases ['writers' such as SET and MYND domain containing 2 (SMYD2), SETD1A and SETDB1] and demethylases ['erasers' such as K demethylase 6A/B (KDM)6A/B and KDM8], and is recognized by specific 'reader' proteins (such as CHD1 and BPTF) (67). Aberrant histone methylation is closely linked to tumor development and serves a key role in metabolic reprogramming (69).

As with RNA methylation, histone methylation enzymes can deposit methyl marks (such as H3K4me3, H3K9me3 and H3K27me3) at the promoters or enhancers of genes involved in lactate metabolism, thus regulating their transcription. In cervical cancer, SMYD2 suppresses p53 transcriptional activity via K370 methylation, thereby impairing its tumor suppressive function. This modification also downregulates genes involved in OXPHOS, shifting tumor metabolism toward glycolysis, as evidenced by increased glucose uptake and lactate production (70). In gastric cancer, SMYD2 enhances apolipoprotein C1 expression through H3K4me3 modification, promoting glycolysis and cell proliferation (71). Similarly, SETD1A, another H3K4 methyltransferase, interacts with HIF-1α to increase its transcriptional activity, thereby upregulating the expression of glycolytic genes such as GLUT1, HK2 and LDHA, and ultimately accelerating tumor glycolysis and progression (72).

SETDB1 serves dual regulatory roles in breast cancer. It promotes the nuclear transport-dependent activation of the c-MYC/LDHA axis and directly methylates LDHA at K155 (73). Notably, SETDB1 also catalyzes K473 trimethylation on MCT1, a novel PTM that blocks Toll-interacting protein-mediated autophagic degradation, prolonging the MCT1 half-life. The resulting increase in lactate secretion maintains high glycolytic flux in tumor cells and induces M2 polarization of tumor-associated macrophages (TAMs) via G protein-coupled receptor (GPR)132 activation, linking tumor metabolic reprogramming with immune microenvironment remodeling (42).

Demethylases also serve pivotal roles in lactate metabolism. KDM6A/B promotes the expression of glycolytic genes such as GLUT1, HK2 and LDHA by removing H3K27me3 marks, enabling detached tumor cells to maintain their glycolytic activity and energy supply during metastasis (74). JMJD5 contributes to metabolic adaptation under hypoxia by demethylating H3K36me2, thereby stabilizing HIF-1α and facilitating PKM2-dependent glycolysis (75).

Histone acetylation is a key epigenetic modification that regulates chromatin structure and gene expression, and serves a pivotal role in various biological processes. In the context of tumor metabolic reprogramming, histone acetylation is closely linked to lactate metabolism, influencing cancer cell energy production, shaping the TME and contributing to therapeutic resistance (76). This modification is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes not only acetylate histones but also target non-histone proteins, including metabolic enzymes and transcription factors, thereby altering their activity, stability or subcellular localization. Through these mechanisms, HATs and HDACs modulate the glycolytic pathway and lactate production, ultimately promoting metabolic adaptation in tumor cells (77).

HATs catalyze the acetylation of K residues on histone tails and non-histone proteins, thereby modulating their transcriptional activity and participating in diverse biological processes. HATs are broadly classified into three major families on the basis of their structural and functional features: GCN5-related N-acetyltransferase, MYST and p300/CREB-binding protein (CBP). Dysregulation of HAT activity has been closely associated with the initiation and progression of multiple types of cancer (78).

The MYST family, a highly conserved class of HATs, includes KAT5 (Tip60), KAT6A, KAT6B, KAT7 (HBO1/MYST2) and KAT8. These enzymes contain a characteristic MYST domain composed of an acetyl-CoA binding motif and a zinc finger, enabling the acetylation of nuclear and cytoplasmic proteins involved in chromatin remodeling, transcription regulation, DNA damage repair and tumorigenesis (79). KAT5 (Tip60) acetylates both histone and non-histone substrates, and serves a critical role in chromatin dynamics and the DNA damage response (80). In cancer cells exhibiting elevated lactate production due to the Warburg effect, KAT5 directly interacts with nibrin (NBS1) and catalyzes lactylation at K388, promoting the assembly of the MRE11-RAD50-NBS1 complex. This enhances DNA repair efficiency and contributes to chemoresistance (81). KAT7 (HBO1) requires association with scaffold proteins such as bromodomain and PHD finger containing 1 or jade family PHD finger 1 to exert its function. Depending on the complex formed, KAT7 acetylates histone H3 (at K14 and K23) or H4 (at K5, K8 and K12), participating in physiological processes such as DNA replication, transcription regulation, protein ubiquitination, immune modulation and stem cell pluripotency (82). Notably, KAT7 acetylates LDHA at K118, increasing its enzymatic activity and expression. This promotes lactate production and facilitates tumor proliferation and metastasis in head and neck squamous cell carcinoma (HNSCC), acting as a pro-oncogenic factor (83).

The p300/CBP family comprises two paralogous coactivators, CBP and p300, each containing a bromodomain. These HATs regulate a wide array of transcription factors, including HIF-1α, and are essential for cell cycle progression, differentiation and growth, with strong implications for cancer development (84,85). In multiple myeloma, acute inhibition of p300/CBP reduces histone acetylation and promotes chromatin condensation, resulting in transcriptional repression. However, this suppression can be antagonized by the loss of the nuclear receptor corepressor 1 (NCOR1)/HDAC3 corepressor complex, identifying NCOR1 and HDAC3 as key modulators of p300/CBP activity (86). In lung cancer, Notch1 interacts functionally with p300 and p300/CBP-associated factor (PCAF) to upregulate glycolytic gene expression. Moreover, it forms a positive feedback loop with TAZ, whereby the Notch1/TAZ axis promotes glycolysis, enhances glucose uptake and lactate production, and suppresses cytotoxic T-cell and natural killer (NK) cell activity, ultimately facilitating immune evasion (87).

In LUAD, upregulation of uridine phosphorylase 1 promotes glycolytic metabolism and reduces sensitivity to the glycolysis inhibitor 2-deoxy-D-glucose (2-DG). This process is epigenetically regulated via p300/CBP-mediated histone acetylation, which contributes to enhanced cancer cell proliferation (88). Furthermore, even under aerobic conditions, cancer cells preferentially rely on glycolysis. PCAF influences cellular energy metabolism through HIF-1α and p53-dependent regulation of SCO2 and TIGAR expression. Notably, the effects of PCAF vary by cellular context: In the human osteosarcoma cell line U2OS, PCAF HAT activity increases glycolysis and lactate production, whereas in SaOS2 osteosarcoma cells, it suppresses these processes (89). These tissue-specific effects may be explained by differences in chromatin accessibility at glycolytic gene loci, as well as variations in acetyl-CoA availability, the essential substrate for PCAF-mediated acetylation (90). Together, these findings underscore the tight coupling between epigenetic regulation and metabolic state, highlighting the importance of cellular context in shaping metabolic phenotypes in cancer. The mechanisms underlying the tissue-specific effects of PCAF include: First, PCAF must access the regulatory regions of its target genes to function; in U2OS cells, the promoters of glycolysis-related genes may exist in an open chromatin state, allowing PCAF binding and transcriptional activation. By contrast, the same regions in SaOS2 cells might be embedded in heterochromatin or carry pre-existing repressive histone marks, preventing PCAF access or nullifying its activation function (91). Second, the enzymatic activity of PCAF is directly influenced by substrate availability. The catalytic substrate of PCAF is acetyl-CoA, a central metabolic metabolite. U2OS cells may maintain higher acetyl-CoA levels, providing ample 'fuel' for PCAF HAT activity, and thereby promoting acetylation and activation of glycolytic genes. Conversely, lower acetyl-CoA levels in SaOS2 cells may restrict the activity of PCAF (92).

HDACs are enzymes that remove acetyl groups from K residues on histones, thereby regulating chromatin structure and gene expression. HDACs are grouped into four classes (I-IV) and include 18 isoforms. In addition to their roles in controlling cell proliferation and differentiation, HDACs influence non-histone protein acetylation in the nucleus, cytoplasm and mitochondria (84,93).

ncRNAs serve pivotal roles in regulating gene expression and tumor metabolism through direct interactions with DNA, RNA and proteins. In particular, ncRNAs contribute to tumor growth by modulating glycolysis and lactate metabolism. They influence the activity of key glycolytic enzymes, alter metabolic reprogramming and affect various signaling pathways, thereby regulating the production, transport and utilization of lactate. By targeting critical enzymes involved in glycolysis and participating in signaling cascades, ncRNAs exert notable control over glucose metabolism, which in turn promotes tumor initiation and progression. Furthermore, metabolic reprogramming driven by ncRNAs provides malignant tumors with the necessary energy to sustain rapid proliferation and metastasis, making them promising targets for novel cancer therapies.

Enhanced glycolysis is a hallmark of cancer metabolism. Notably, viral infections can also hijack this metabolic pathway, promoting aerobic glycolysis to support viral replication. lncRNAs serve critical roles in regulating glycolysis and lactate metabolism through diverse molecular mechanisms, thereby influencing tumor initiation, progression, metastasis and therapeutic response (112).

Multiple studies have revealed that lncRNAs modulate glycolytic enzyme expression, stabilize mRNAs, interact with signaling proteins and act as competing endogenous RNAs (ceRNAs) to regulate metabolic pathways. Protein interactions are essential for lncRNA-mediated metabolic regulation. For example, HULC binds to both LDHA and PKM2, thereby facilitating aerobic glycolysis and tumor growth of HCC (113). In liver cancer cells, LINC01419 interacts with Y-box binding protein 1 to stabilize PDK1 mRNA, promoting lactate production and metabolic reprogramming (114). Additionally, in the context of m6A modification, the m6A reader IMP2 stabilizes the lncRNA ZFAS1, which in turn activates the OLA1 axis and enhances glycolysis, contributing to CRC progression (115). lncRNAs also regulate glycolysis by interacting with miRNAs. For example, CASC9 negatively regulates miR-383-5p, which targets LDHA, thus indirectly increasing LDHA levels. While this mechanism has been studied in the context of spinal cord injury, the regulatory axis may have broader implications in cancer and other diseases (116). In osteosarcoma, a risk model was constructed from differentially expressed lncRNAs associated with lactate metabolism pathways (117), and RP11-472M19.2 was identified as an important regulator of immune infiltration and metastasis by modulating chemokine expression and glycolysis. RP11-472M19.2 upregulates LDHA-mediated lactate production, which promotes an immunosuppressive microenvironment and supports tumor metastasis (117). In cervical cancer, NEAT1 is consistently upregulated; its silencing inhibits glycolysis and cellular aggressiveness, whereas its overexpression has the opposite effect. Mechanistically, NEAT1 upregulates PDK1 via the WNT/β-catenin pathway and stabilizes the β-catenin protein without affecting its mRNA level. RNA pull-down assays have excluded direct interactions between NEAT1 and the β-catenin protein (118). In LUAD, HOXA11-AS promotes proliferation and glycolysis via the miR-148b-3p/PKM2 axis (119). Furthermore, lactate can be metabolized within tumor cells to sustain growth, and lncRNAs markedly influence lactate reutilization.

The immune microenvironment also exhibits lncRNA-mediated glycolytic regulation. PVT1, for example, is upregulated during CD4⁺ T-cell activation and enhances glycolytic reprogramming (120). The macrophage-derived lncRNA HISLA is transmitted to breast cancer cells via extracellular vesicles, where it stabilizes HIF-1α to drive aerobic glycolysis and apoptotic resistance. This creates a metabolic feed-forward loop in the tumor microenvironment, as tumor-derived lactate reciprocally upregulates HISLA in macrophages to fuel chemoresistance and disease progression (121). In breast cancer, TAMs deliver the lncRNA HISLA via extracellular vesicles, stabilizing HIF-1α in cancer cells, and promoting aerobic glycolysis and resistance to apoptosis (121). In addition, HITT directly interacts with PKM2 in HCC, preventing its oligomerization, reducing pyruvate kinase activity, and consequently suppressing lactate production and tumor growth while modulating macrophage polarization (122). The exosomal lncRNA TUG1, which is secreted by cancer-associated fibroblasts (CAFs), enhances glycolysis and lactate metabolism in HCC via the miR-524-5p/SIX1 axis, highlighting the key regulatory roles of lncRNAs within the TME (123).

lncRNAs form a sophisticated regulatory network for glycolysis and lactate metabolism through multiple molecular mechanisms, including direct binding to metabolic enzymes, functioning as ceRNAs to sequester miRNAs and mediating intercellular communication within the TME. By remodeling the energy metabolism of tumor cells, these lncRNAs have pivotal roles in driving tumor progression, immune evasion and therapy resistance.

Lactate metabolism is regulated by key enzymes such as LDHA, HK2, PFK1 and PKM2. Pharmacological inhibition of these enzymes can reduce lactate production, increase oxidative metabolism and ultimately impede tumor progression (21). Among them, CHK-336, a first-in-class orally bioavailable LDHA inhibitor that has been evaluated in a first-in-human clinical study, represents the only reported clinical agent targeting lactate metabolism (183); however, its antitumor efficacy in patients with cancer remains to be fully established.