Common epigenetic modifications in HCC progression include DNA methylation and histone modification (17). The regulation of epigenetic modification determines the function of lncRNAs. lncRNAs can recruit some chromatin remodeling complexes to mediate gene silencing and thus play a role in promoting or suppressing HCC. For example, linc00441 has been shown to recruit DNA methyltransferase (DNMT)3A for methylation, inducing the silencing of its neighboring gene, RB1, and thereby promoting the proliferation of HCC cells (18). In addition, DNMT1 and DNMT3 induce the hypermethylation of the MEG3 promoter of the tumor suppressor lncRNA, reducing MEG3 expression and leading to apoptotic resistance and tumor growth in HCC cells (19). Of note, Zhou et al (20) reported that lncRNA ID2-AS1 inhibited HCC tumor metastasis by blocking histone deacetylase 8.

Different forms of selective splicing of lncRNA precursors (pre-lncRNAs) generate different isoforms of lncRNAs, which may enable them to perform different functions in HCC. For example, lncRNA PXN-AS1 can be spliced into several different isoforms, among which the PXN-AS1-L isoform inhibits apoptosis in myeloid leukemia in a PXN-dependent manner (21). However, another isoform (PXN-AS1-IR3) promotes HCC metastasis by inducing transcriptional activation of MYC (22). In addition, the lncRNA NEAT1 can be alternatively spliced to produce two isoforms, NEAT1_1 and NEAT1_2. It has been found that the low expression of NEAT1_2 is significantly associated with the overall survival of patients with HCC. Follow-up data suggest that NEAT1_2, but not NEAT1_1, mediates mTORC1 signaling to control aerobic glycolysis in HCC cells, contributing to the Warburg effect and HCC development (23).

lncRNAs are subject to different transcriptional regulations, which markedly affect the cancer- or cancer-suppressive functions of lncRNAs. A number of tumor suppressor genes or oncogene transcription factors, including p53, hypoxia inducible factor-1α (HIF-1α) and myelocytomatosis (myc) have been shown to induce the transcription of lncRNA genes. For example, myc is a key proto-oncogene, and in HCC, lncRNA linc00176, which is transcribed by myc, has been found to play a role in promoting cell proliferation and survival by inhibiting cancer cell cycle arrest and cell necrosis (24). Another study demonstrated that HIF-1α binds to the promoter region of lncRNA RAET1K to activate its transcription, thereby enhancing its cancer-promoting effect in HCC (25). However, MEG3 has been identified to function as a tumor suppressor gene in hepatoma cells by interacting with tumor suppressor p53 protein to activate p53-mediated transcriptional activity and affect the expression of certain p53 target genes (26).

The binding of lncRNAs to RNAs is another key factor in determining their role in cancer. ALKBH3-AS1 is a carcinogenic lncRNA, which directly binds ALKBH3 mRNA in HCC cells, upregulates the expression level of ALKBH3, and promotes the proliferation of cancer cells (27). In addition to directly regulating mRNAs, lncRNAs also affect the expression of their target genes by controlling microRNA (miRNA or miR) expression. For example, it has been demonstrated that lncRNA XIST binds miR-92b as a sponge in liver cancer tissues, preventing miR-92b from binding to its downstream target Smad7 mRNA, thereby inhibiting the proliferation and metastasis of HCC (28).

Encoded small peptides play a crucial role in cancer development and determine the functions of lncRNAs in cancer. SMIM30, encoded by LINC00998 in HCC, has been found to be associated with a low survival rate of patients with HCC and is able to promote the development of HCC by inducing SRC/YES1 membrane anchoring and MAPK pathway activation (29). By contrast, LINC-PINT encodes a PINT87aa micropeptide that binds to the transcription factor, FOXM1, as a potential anticancer micropeptide, while promoting cancer cell senescence (30). A recent correlative study using ribosome analysis methods found that a 99-aa peptide termed KRASIM encoded by lncRNA NCBP2-AS2 bound to KRAS proteins to inhibit ERK signaling, thereby inhibiting the growth of HCC cells (31).

Aerobic glycolysis in HCC cells has been reported to be closely related to their sustained proliferation, invasive metastasis, the induction of stem cell activity and the generation of therapeutic resistance. In the aerobic glycolytic metabolism of HCC cells, an increase in the glycolytic flux of the cancer cells, accompanied by an increase in intermediate metabolites, provides sufficient energy and metabolites for the biosynthetic molecules required for the sustained proliferation of the cancer cells. As previously demonstrated, in xenograft tumors, the growth rate of HCC tumors was reduced by ~50% by decreasing the aerobic glycolytic enzyme, hexokinase 2 (HK2) (32). The production of large amounts of lactate and H⁺ in aerobic glycolysis leads to the acidification of the extracellular environment, induces the transformation of cancer cell epithelial cells into mesenchymal cells, and promotes the invasion and metastasis of tumor cells. It has been found that the highly metastatic HCC cell lines, MHCC97H and LM3, exhibit higher levels of aerobic glycolysis compared with those with a lesser invasive ability (33). Increased lactate levels further enhance the stemness of tumor stem cells, and the elevated lactylation of H3 histone effectively promotes the oncogenicity of HCC stem cells ⁽34). Furthermore, the substantial production of lactic acid and hydrogen ions (H⁺) during aerobic glycolysis leads to acidification of the tumor microenvironment, promoting immunosuppression and facilitating tumor immune evasion, as well as conferring resistance to immunotherapy (35). Therefore, targeting glycolytic metabolic pathways and controlling lactate levels may be an effective strategy with which to prevent or attenuate the progression of HCC.

In the tumor microenvironment, some lncRNAs can affect proliferation, metastasis and drug resistance in HCC by promoting or inhibiting aerobic glycolysis in tumor cells. For example, the knockdown of NPSR1-AS1 in HCC cells has been shown to reduce their glycolytic metabolism and abolish their tumorigenic potential. This suggests that NPSR1-AS1 has glycolysis-dependent tumorigenic activity in HCC (36). It has been demonstrated that overexpression of lncRNA RP11-620J15.3 in HCC suggests that it functions as a competitive endogenous RNA to upregulate glucose-6-phosphate isomerase via sponge-binding to miR-326 and promoting aerobic glycolysis, which in turn promotes HCC cell proliferation and metastasis (37). In addition to promoting tumor progression, targeting changes in cancer cell metabolism is currently providing new insight into tumor drug therapy. Tretinoin is a widely known compound capable of inhibiting the development of HCC. Zhang et al (38) demonstrated that lncRNA MBNL1-AS1 reduced the sensitivity of HCC cells to tretinoin by inhibiting miR-708-5p-mediated glycolysis. This finding revealed an effective therapeutic target for the treatment of HCC. The majority of the lncRNAs involved in glycolysis in HCC are summarized in Table I and are discussed below.

HOTAIR is a new class of oncogenic lncRNA often involved in regulating chromatin remodeling and epigenetic changes (66). Previous research has indicated that HOTAIR is highly expressed in a variety of malignant tumors and is involved in cell proliferation, metastasis, DNA repair and metabolism (67). As previously demonstrated in HCC, HOTAIR promotes glycolysis through the upregulation of glucose transporter (GLUT)1 and the activation of the mTOR signaling pathway (42). In addition, has been revealed to promote glycolysis in HCC under hypoxic conditions by targeting and inhibiting miR-130a-3p (41).

The lncRNA UCA1 was originally identified in human bladder cancer. It has an aberrant expression in embryogenesis and in a wide range of cancerous tissues and cells, and plays a role in tumor growth and glycolysis (68). The expression of UCA1 has been found to be higher in HCC tissues than in paracancerous tissues. Upwardly mobile coding protein 1 (UPF1) is an evolutionarily conserved and ubiquitously expressed phosphoprotein that promotes cellular processes through G1/S (69). RIP experiments have revealed that UPF1 specifically binds to UCA1, and the downregulation of UPF1 significantly upregulates the expression level of UCA1 and effectively increases the rate of lactate production in HCC (70).

TCF7L2 has been identified to be an effector of the Wnt signaling pathway and directly binds to several genes which play a key role in the regulation of glucose metabolism. In addition, genome-wide association studies have identified single nucleotide polymorphisms in the TCF7L2 gene associated with diabetes mellitus (71). It has been previously indicated that MALAT1 plays a pivotal role in the regulation of HCC cell proliferation, migration, and metastasis (72). Furthermore, MALAT1 has been found to regulate the expression of glycolytic genes in HCC by increasing the translation of the transcription factor, TCF7L2, which increases lactate and glucose fluxes (43). In addition, gluconeogenesis, a major component of normal hepatocyte glucose metabolism, is negatively regulated by MALAT1.

LINC01554 is a tumor suppressor lncRNA and inhibits aerobic glycolysis in HCC (61). The primary target of LINC01554 is pyruvate kinase M2 (PKM2), which is the late rate-limiting enzyme of aerobic glycolysis. In vitro ubiquitination experiments demonstrated enhanced PKM2 degradation mediated by ubiquitination in LINC01554 cells compared with controls. In LINC01554-KO cells, the ubiquitination-mediated degradation of PKM2 by LINC01554 was significantly attenuated. This resulted in a reduced glucose consumption, lactate production and pyruvate production, and in increased ATP levels. LINC01554 has the characteristic of weakening the advantage of cancer cells in acquiring high glycolysis; therefore, LINC01554 functions as a tumor suppressor in HCC and may be used as a potential therapeutic target in patients with HCC.

HK catalyzes the first step in glycolytic metabolism, catalyzing the formation of glucose-6-phosphate. It is considered to be a key regulator of cellular energy metabolism and contributes to the Warburg effect by promoting intracellular glucose uptake (81–83). HK2 has often been reported to be highly expressed in HCC cells and induces tumor development by promoting glycolysis. The lncRNA TUG1 has been shown to be significantly associated with HK2 overexpression and the poor prognosis of patients with HCC. It has also been demonstrated that TUG1 positively regulates HK2 expression by binding to miR-455-3p, which promotes glycolysis in tumor cells, and accelerates tumor growth and metastasis (40). In addition, MBNL1-AS1 and NR2F1-AS1 have been reported to positively regulate the expression level of HK2, which promotes aerobic glycolysis in HCC cells, and contributes to cancer cell proliferation, migration and resistance to therapeutic drugs (38,50). Therefore, an in-depth study of HK2 may provide insight into the tumorigenesis and progression of HCC, and may lead to the development of novel therapeutics.

LDHA is a member of the LDH family, which is the rate-limiting enzyme for the interconversion of pyruvate and lactate in the glycolytic pathway. LDHA is upregulated in a number of types of cancer and is associated with the clinicopathological features and prognosis of patients (84,85). The lncRNA RAET1K has been found to be positively associated with the expression of LDHA in cells and regulate its activity, contributing to increased levels of glycolysis, thereby promoting cell proliferation and invasion (25).

PK functions as the final rate-limiting enzyme of glycolysis, converting phosphoenolpyruvate to pyruvate. PKM2 is one of the four isozymes of PK and plays a crucial role in cancer development (86). lncRNAs can participate in the regulation of aerobic glycolysis by affecting the expression of PKM2, thereby influencing HCC progression. For example, the lncRNA SOX2OT has been shown to promote PKM2-mediated glycolytic activation by targeting the binding to miR-122-5p, increasing its expression level and promoting the metastasis of HCC cells (48). In addition, the lncRNA SNHG1 has been revealed to function as a molecular sponge for miR-326, isolating the interaction of miR-326 with PKM2, and promoting PKM2 expression. The activation of PKM2 expression is one of the mechanisms through which SNHG1 promotes glycolysis and HCC cell proliferation (56). NONHSAT024276, a potential oncogene for HCC, directly binds to polypyrimidine bundle-binding protein 1 (PTBP1), increases the ratio of M1 to M2 isoforms of PKM1/PKM2 and blocks PTBP1/PKM-mediated glycolysis to inhibit cancer cell proliferation and migration (63).

PFKFB4, a member of the PFKFB family, which has been identified to be a key regulator of glycolysis, controls the synthesis and degradation of fructose-2,6-bisphosphate (F-2,6-BP) (87). It has been recently revealed that lncRNAs are involved in the regulation of PFKFB4 expression in tumor tissues and that they play a key role in tumor glycolysis. The high expression of the lncRNA FIRRE has been shown to be associated with malignant clinical features and with the poor survival of patients with HCC. Mechanistically, FIRRE promotes HCC cell proliferation and glycolysis by facilitating PFKFB4 transcription and expression, mainly through cAMP-responsive element-binding protein (53). Another study confirmed that LINC01572 is aberrantly upregulated in HCC tissues, particularly in patients with type 2 diabetes. Mechanistically, LINC01572 increases the level of PFKFB4 by competitively inhibiting miR-195-5p, thereby enhancing glycolysis and triggering HCC development (54).

p53 (also known as TP53) is a well-known tumor suppressor gene. It has been demonstrated that lncRNAs, as functional components of the p53 pathway, may play a regulatory role in this pathway. lncRNA CERS6-AS1 can sponge miR-30b-3p to elevate MDM2, which promotes MDM2-mediated ubiquitin-dependent degradation of the p53 oncogene, and facilitates glycolysis in HCC cells (57). On the contrary, the interaction between p53 and lncRNA can promote cancer by influencing glycolytic enzymes. p53 forms a complex with the lncRNA CUDR, which binds to the promoter region of PKM2 to enhance PKM2 expression, phosphorylation and polymer formation, and, ultimately, p53 accelerates the growth of the HCC cell line, Hep3B, by lengthening telomeres through a cascade of reactions that promotes HCC development (88).

c-Myc is a transcription factor, mainly found in the nucleus, that has been implicated in the development and progression of cancer. c-Myc, as a major regulator of aerobic glycolysis, can regulate aerobic glycolysis by directly activating glycolytic enzymes (89). In addition to a large number of coding genes, lncRNAs function as downstream targets of c-Myc and participate in glycolysis in cancer cells. lncRNA FTO-IT1 has been shown to enhance glycolysis in HCC by inducing the stabilization of FTO mRNA, leading to the overexpression of c-Myc. Moreover, c-Myc has been found to regulate the expression of FTO-IT1 by binding to its promoter region under low glucose conditions, forming a positive feedback loop between c-Myc and FTO-IT1 (47). Wu et al (58) also demonstrated that MNX1-AS1, a c-Myc target gene, was upregulated in HCC, promoting aerobic glycolysis and tumorigenesis.

When tumor cells continue to proliferate and expand to a certain limit, vascular hypoxia leads to the appearance of HIF, and HIF-1α plays a key role as a member of the aerobic glycolysis and lactate pathways (90). In hypoxic environments, NPSR1-AS1 induces the activation of the MAPK/ERK pathway in HCC cells, which promotes the proliferation and glycolysis of HCC cells (36). The overexpression of lncRNA UPK1A-AS1 has been reported to significantly increase the stability of the HIF-1α ubiquitin-modified expression of upregulated glycolysis-related genes, thereby promoting glycolysis levels in HCC cells (59).

The dysregulation of the PI3K/AKT/mTOR pathway is a prevalent occurrence in the majority of human cancers. In HCC, this signaling cascade plays a crucial role in facilitating glucose metabolism, tumor metastasis, and resistance to drugs (91–93). It has been demonstrated that lncRNA is a regulator of PI3K/AKT/mTOR signaling in a variety of cancer types, and can indirectly affect the expression of enzymes by regulating this pathway. In HCC tissues and cell lines, the upregulation of LINC01572 increases the expression of the glycolytic enzyme, PFKFB4, by activating PI3K/AKT signaling, thereby enhancing glycolysis and triggering HCC malignancy (54). mTOR is a serine/threonine kinase. It has been previously shown that the upregulation of lncRNA HOTAIR can induce the glycolysis of HCC cells by activating the mTOR signaling pathway (42). By contrast, LINC01554, a novel oncogene in HCC, has been identified to inhibit the AKT/mTOR signaling pathway and eliminate aerobic glycolysis in HCC cells, thereby suppressing tumor growth (61).

In summary, lncRNAs mediate changes in the expression of glycolysis-associated transporter proteins, enzymes and signaling pathways in HCCs, affecting the level of tumor aerobic glycolysis, and thus cancer formation and progression. Therefore, these glycolysis-associated lncRNAs have gradually become key targets for cancer research, and the inhibition of these lncRNAs is critical for controlling tumor development. Follow-up studies should continue to explore the mechanisms of the lncRNA regulation of glycolysis to provide new directions for cancer treatment.