Deciphering the role of taurine-upregulated gene 1 in liver diseases: Mechanisms, clinical relevance, and emerging therapeutic opportunities

Abstract

Liver diseases are progressive conditions driven by multiple factors, including molecular regulators such as nonprotein-coding RNAs, which orchestrate genetic and epigenetic processes across various biological levels. Long noncoding RNAs (lncRNAs), RNA molecules longer than 200 nucleotides, have been identified as key modulators in both cancerous and noncancerous liver diseases. Among them, taurine-upregulated gene 1 (TUG1), one of the earliest discovered lncRNAs, has emerged as a tumor promoter in hepatocellular carcinoma. Functionally, TUG1 exerts its regulatory effects primarily through microRNA sponging as a competing endogenous RNA while also exhibiting protein-binding capabilities that suggest additional roles in both transcriptional and posttranscriptional regulation. Furthermore, evidence suggests that dysregulation of TUG1 is closely linked to the development and progression of liver diseases. This review explores the key characteristics, mechanisms, and signaling pathways through which TUG1 affects liver disease, offering fresh insights into potential therapeutic directions and new avenues for future TUG1-related research.

Key Words: Taurine-upregulated gene 1; MicroRNA; Long noncoding RNA; Liver disease; Hepatocellular carcinoma

Core Tip: Taurine-upregulated gene 1 (TUG1), a long noncoding RNA, plays a critical role in liver pathogenesis by regulating gene expression through diverse mechanisms, including acting as a microRNA sponge, interacting with proteins, and modulating signaling pathways. TUG1 is involved in various liver diseases, including hepatocellular carcinoma, liver injury, fibrosis/cirrhosis, and metabolic dysfunction–associated steatotic liver disease, making it a potential therapeutic target.

INTRODUCTION

Liver diseases pose an overwhelmingly high mortality burden, with cirrhosis, hepatitis, and liver cancer accounting for approximately 2 million deaths annually[1]. According to predictive modeling studies, the incidence and mortality rates are projected to continue to rise for metabolic dysfunction–associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC) in the coming decades[2-4]. It is anticipated that liver disease-related mortality may increase due to the obesity epidemic and the progressive aging of the global population[5,6]. In addition to compromising patient quality of life, liver diseases also impose a substantial burden on both individual finances and the national economy[7,8].

Over decades of research, studies have emphasized the pivotal role of protein-coding genes as "driver genes" in disease progression[9,10]. However, protein-coding regions constitute only a small fraction of the human genome (approximately 2%), while the majority of these regions are transcribed into noncoding RNAs (ncRNAs)[11]. These ncRNAs can be broadly classified into two main groups: (1) Housekeeping ncRNAs (e.g., ribosomal RNAs, transfer RNAs, small nuclear RNAs, and small nucleolar RNAs); and (2) Regulatory ncRNAs, which are tightly regulated [e.g., microRNAs (miRNAs) and long ncRNAs (lncRNAs)][12,13]. These ncRNAs play diverse roles in regulating gene expression across multiple levels under both physiological and pathological conditions[14-16], including liver diseases[17-19].

LncRNAs, which are generally defined as transcripts longer than 200 nucleotides with no protein-coding potential, have emerged as important regulators of gene expression under both physiological and pathological conditions[20]. Their genetic diversity is approximately twice as high as that of protein-coding transcripts[21]. Most lncRNAs are generated by RNA polymerase II (Pol II), and many of them undergo splicing and polyadenylation, which leads to their description as “mRNA-like”[22]. Moreover, loci expressing lncRNAs could exhibit some characteristics of protein-coding genes, such as multiple exons and promoters[23].

In contrast to mRNAs, lncRNAs generally exhibit more restricted expression patterns, are highly cell lineage specific, and are less evolutionarily conserved[22,24,25]. They have also been described to be closely related to developmental stage or disease-stage-specific patterns[26,27]. Through interactions with DNA, RNA, and proteins, lncRNAs regulate gene expression at multiple levels via a diverse array of molecular mechanisms[28,29]. These interactions allow lncRNAs to participate in critical processes such as chromatin organization, transcriptional regulation, and posttranscriptional modification[29,30]. Consequently, lncRNAs have garnered significant attention as pivotal elements in understanding the complexities of cell biology. Although lncRNAs are often expressed at low levels, their regulatory potential remains biologically significant and warrants further investigation to clarify how lncRNAs exert their regulatory effects[31].

Dysregulated expression of lncRNAs is intricately linked to the development of human diseases[32,33]. Similarly, numerous studies have emphasized the role of lncRNAs in initiating and advancing liver disease, aiming to provide insights into their involvement in key physiological and pathological processes in the liver[34,35]. Therefore, significant efforts have been made to explore lncRNA candidates as potential therapeutic targets, aiming to bridge knowledge gaps and develop therapeutic approaches[36-40]. In this review, we provide a focused exploration of the long noncoding RNA taurine-upregulated gene 1 (TUG1), detailing its mechanisms of action and emerging evidence supporting its regulatory roles in liver diseases.

LNCRNA BIOGENESIS

Most lncRNAs are transcribed by RNA Pol II and resemble mRNAs in features such as 5' capping, 3' polyadenylation, and splicing (Figure 1)[29]. Despite these similarities, they are spliced less efficiently[41,42], possibly because of weaker internal splicing signals and larger distances between the branch point and 3’ splice site[43]. Additionally, chromatin-associated lncRNAs harbor multiple U1 small nuclear RNA binding sites, promoting Pol II activity through U1 small nuclear ribonucleoprotein[44]. Some also contain sequence motifs or repeat elements. For example, some contain a nuclear retention element[45], whereas others have an Alu repeat with a C-rich sequence that facilitates interaction with the nuclear matrix protein heterogeneous nuclear ribonucleoprotein K[46]. Moreover, repeating RNA domains can promote association with heterogeneous nuclear ribonucleoprotein U[47]. These features likely explain their primary nuclear localization. However, localization is not strictly nuclear. Under specific conditions, some lncRNAs are exported and accumulate under specific conditions to perform their molecular functions[29]. Notably, a previous study revealed that most lncRNA transcripts, particularly those with fewer, longer exons or high A/U content relative to mRNAs, preferentially rely on nuclear RNA export factor 1 for nuclear export[48]. However, the specific sorting mechanism responsible for lncRNA cytoplasmic localization is not fully understood.

Figure 1 Biogenesis and diverse functions of long noncoding RNAs. This schematic illustrates how long noncoding RNAs (lncRNAs) are transcribed, processed, and function. Most lncRNAs are transcribed by RNA polymerase II, undergo 5' capping, 3' polyadenylation, and less efficient splicing. Some lncRNAs localize to the nucleus and act as decoys or scaffolds, while others are exported to the cytoplasm. In the cytoplasm, lncRNAs can regulate gene expression by interacting with proteins or microRNAs. LncRNAs: Long noncoding RNAs; MiRNA: MicroRNAs; NRE: Notopterygium incisum root extract; NXF: Nuclear RNA export factor 1; Pol II: Polymerase II; RBP: RNA-binding protein.

TUG1 CHARACTERISTICS

Initially discovered through microarray screening, the long intergenic RNA TUG1, an approximately 7-kb transcript localized to chromosome 22q12.2, was identified by its upregulation upon taurine treatment, a cysteine derivative crucial for neural development[49,50]. Its early functional role was demonstrated in the development of mouse retinal cells[50]. The functional repertoire of TUG1 subsequently expanded, as studies revealed regulatory roles in male fertility and the presence of a coding isoform affecting the mitochondrial membrane potential[51]. Like other lncRNAs, TUG1 employs diverse molecular mechanisms to regulate gene expression. It has been shown to interact with polycomb repressive complex 2 (PRC2) to control the cell cycle[52,53] and with peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) to modulate mitochondrial bioenergetics[54] or miRNAs to inhibit their biological functions[49]. Given these diverse activities, TUG1 has been implicated as one of the key contributing factors in various human diseases, such as Friedreich ataxia[55], particulate matter-induced epithelial injury[56], myocardial infarction[57], infantile hemangioma[58], and atherosclerosis[59]. In the context of cancer, accumulating evidence indicates that TUG1 primarily acts as a competitive endogenous RNA (ceRNA), sequestering tumor suppressor miRNAs and impairing their regulatory activities. Its overexpression is commonly observed in cancers, including esophageal carcinoma[60], pancreatic cancer[61], osteosarcoma[62], colorectal cancer[63], bladder cancer[64], and HCC[65-67]. These findings demonstrate that TUG1 could influence downstream target elements, thereby altering cellular physiopathology.

THE INVOLVEMENT OF THE TUG1 REGULATORY MECHANISM IN HCC

As one of the leading high-mortality cancers, HCC remains a global health threat due to its biological heterogeneity, poor postsurgical prognosis, and risk of tumor recurrence, emphasizing the need for further research into its biology. Table 1 summarizes the diverse molecular functions and regulatory axes of TUG1[65-87]. Figure 2 illustrates its regulatory interactions.

Figure 2 Taurine-upregulated gene 1 regulatory network in hepatocellular carcinoma. This diagram illustrates the complex interplay between taurine-upregulated gene 1 (TUG1) and various genes, microRNAs (miRNAs), and signaling pathways in hepatocellular carcinoma. TUG1 modulates the expression of oncogenes and tumor suppressors (e.g., mucin 1, collagen type I alpha 1, interferon induced transmembrane protein 1), influencing cellular processes like proliferation, metastasis, and apoptosis. TUG1 acts as a competitive endogenous RNA by sponging miRNAs (e.g., miR-4726-5p, miR-29c-3p), thereby regulating their target genes. Additionally, TUG1 interacts with transcription factors (e.g., triiodothyronine/thyroid hormone receptors, specificity protein 1) and epigenetic modifiers (e.g., polycomb repressive complex 2 complex) to control gene expression. Red arrows indicate activation, and T-bars indicate repression (created in BioRender). AFP: Alpha-fetoprotein; AKT2: Protein kinase B 2; AMPKβ2: AMP-activated protein kinase beta 2; AURKA: Aurora kinase A; CD47: C luster of Differentiation 47; COL1A1: Collagen type I alpha 1; CXCR4: C-X-C motif chemokine receptor 4; DLX2: Distal-less homeobox 2; E2F1: E2F transcription factor 1; EZH2: Enhancer of zeste 2 polycomb repressive complex 2 subunit; IFITM1: Interferon induced transmembrane protein 1; IGF1: Insulin like growth factor 1; JAK2: Janus kinase 2; KLF2: Krüppel-like factor 2; MUC1: Mucin 1; P21: Cyclin-dependent kinase inhibitor 1A; PD-L1: Programmed death-ligand 1; PRC2: Polycomb repressive complex 2; ROMO1: Reactive oxygen species modulator 1; RRAGD: Ras related GTP binding D; Shh: Sonic hedgehog; Siglec-15: Sialic acid-binding immunoglobulin-like lectin-15; SIX1: SIX homeobox 1; Sp1: Specificity protein 1; SRSF9: Serine and arginine rich splicing factor 9; SUZ12: Suppressor of zeste 12; T3: Triiodothyronine; TR: Thyroid hormone receptors; TUG1: Taurine-upregulated gene 1; USF1: Upstream stimulatory factor 1; VEGFA: Vascular endothelial growth factor A; YBX1: Y-box binding protein 1; ZEB1: Zinc finger E-box binding homeobox 1.

Table 1 The regulatory axis of taurine upregulated gene 1 in hepatocellular carcinoma.

Function	Pathway	Target miRNA	Target protein	Molecular mechanism	TUG1 role	Ref.
Proliferation, apoptosis, metastasis, angiogenesis
LncRNA-protein interaction	-	-	EZH2/SUZ12/KLF2	SP1-upregulated TUG1 interacts with PRC2 subunit, EZH2 and SUZ12, to suppress KLF2	Tumor-promoting	Huang et al[68]
-	-	-	AFP	Repression of TUG1 mediated by Triiodothyronine reduce AFP expression	Tumor-promoting	Lin et al[69]
LncRNA-protein interaction	-	-	USF1/ROMO1	TUG1 recruits USF1 to ROMO1 promoter, activating its transcription	Tumor-promoting	Liu et al[70]
MiRNA sponge/ceRNA	-	MiR-34a-5p	VEGFA	TUG1 sequesters miR-34a-5p, a negative regulator of VEGFA	Tumor-promoting	Dong et al[71]
MiRNA sponge/ceRNA	Hedgehog signaling pathway	MiR-132	Shh	TUG1 sequesters miR-132, a negative regulator of Shh	Tumor-promoting	Li et al[72]
-	-	-	AURKA	Overexpression of TUG1 is positively correlated with expression of AURKA	Tumor-promoting	Kang et al[73]
MiRNA sponge/ceRNA	Phosphatidylinositol 3-kinase/AKT pathway	MiR-137	AKT2	TUG1 sequesters miR-137, a negative regulator of AKT2	Tumor-promoting	Li et al[74]
MiRNA sponge/ceRNA	-	MiR-142-3p	ZEB1	TUG1 sequesters miR-142-3p, a negative regulator of ZEB1	Tumor-promoting	He et al[75]
MiRNA sponge/ceRNA	JAK2/STAT3 pathway	MiR-144	JAK2	TUG1 sequesters miR-144, a negative regulator of JAK2	Tumor-promoting	Lv et al[76]
MiRNA sponge/ceRNA	JAK2/STAT3 pathway	MiR-204-5p	JAK2	TUG1 sequesters miR-204-5p, a negative regulator of JAK2	Tumor-promoting	Yuan et al[77]
MiRNA sponge/ceRNA	Mammalian target of rapamycin/S6K pathway	MiR-144-3p	RRAGD	TUG1 sequesters miR-144-3p, a negative regulator of RRAGD	Tumor-promoting	Chen et al[78]
MiRNA sponge/ceRNA	-	MiR-216b-5p	DLX2	TUG1 sequesters miR-216b-5p, a negative regulator of DLX2	Tumor-promoting	Dai et al[66]
MiRNA sponge/ceRNA	-	MiR-29a	IFITM3	TUG1 sequesters miR-29a, a negative regulator of IFITM3	Tumor-promoting	Liu et al[79]
MiRNA sponge/ceRNA	-	MiR-29c-3p	COL1A1	TUG1 sequesters miR-29c-3p, a negative regulator of COL1A1	Tumor-promoting	Zhao et al[80]
MiRNA sponge/ceRNA	-	MiR-328-3p	SRSF9	TUG1 sequesters miR-328-3p, a negative regulator of SRSF9	Tumor-promoting	Liu et al[65]
MiRNA sponge/ceRNA	-	MiR-1-3p	IGF1	TUG1 sequesters miR-1-3p, a negative regulator of IGF1	Tumor-promoting	Tang et al[81]
MiRNA sponge/ceRNA	-	MiR-4726-5p	MUC1	TUG1 sequesters miR-4726-5p, a negative regulator of MUC1	Tumor-promoting	Tang et al[82]
Immune response
MiRNA sponge/ceRNA	-	MiR-335-5p	CXCR4	TUG1 sequesters miR-335-5p, a negative regulator of CXCR4	Tumor-promoting	Xie et al[83]
MiRNA sponge/ceRNA	-	MiR-582-5p	Siglec-15	TUG1 sequesters miR-582-5p, a negative regulator of Siglec-15	Tumor-promoting	Ren et al[84]
-	JAK2/STAT3 pathway	-	PD-L1	Overexpression of TUG1 is positively correlated with expression of PD-L1	Tumor-promoting	Wu et al[85]
MiRNA sponge/ceRNA	-	MiR-141, miR-340	PD-L1, CD47	TUG1 sequesters miR-141 and miR-340, which serve as a negative regulator of PD-L1 and CD47, respectively	Tumor-promoting	Xi et al[86]
LncRNA-protein interaction	-	-	YBX1/PD-L1/CD47	TUG1 directly interacts with YBX1 and recruits to the PD-L1 and CD47 promoters, activating their transcription	Tumor-promoting	Xi et al[86]
Glycolysis
LncRNA-protein interaction	-	MiR-455-3p	EZH2/p21/AMPKβ2	By interacting with EZH2 of PRC2, TUG1 silences the p21 promoter, thereby reducing p21 regulation on E2F transcription factor 1, which controls the level of tumor-promoting miR-455-3p targeting AMPKβ2	Tumor-promoting	Lin et al[87]
MiRNA sponge/ceRNA	-	MiR-524-5p	SIX1	TUG1 sequesters miR-524-5p, a negative regulator of SIX1	Tumor-promoting	Lu et al[67]

AFP: Alpha-fetoprotein; AKT: Protein kinase B; AMPKβ2: AMP-activated protein kinase beta 2; AURKA: Aurora kinase A; CD47: Cluster of differentiation 47; CeRNA: Competitive endogenous RNA; COL1A1: Collagen type I alpha 1; CXCR4: C-X-C motif chemokine receptor 4; DLX2: Distal-less homeobox 2; EZH2: Enhancer of zeste 2 polycomb repressive complex 2 subunit; IFITM3: Interferon induced transmembrane protein 3; IGF1: Insulin like growth factor 1; JAK2: Janus kinase 2; KLF2: Krüppel-like factor 2; LncRNA: Long noncoding RNA; MiRNAs: MicroRNAs; MUC1: Mucin 1; P21: Cyclin-dependent kinase inhibitor 1A; PD-L1: Programmed death-ligand 1; PRC2: Polycomb repressive complex 2; ROMO1: Reactive oxygen species modulator 1; RRAGD: Ras related GTP binding D; Shh: Sonic hedgehog; Siglec-15: Sialic acid-binding immunoglobulin-like lectin-15; SIX1: SIX homeobox 1; SRSF9: Serine and arginine rich splicing factor 9; STAT: Signal transducer and activator of the transcription; SUZ12: Suppressor of zeste 12; TUG1: Taurine upregulated gene 1; USF1: Upstream stimulatory factor 1; VEGFA: Vascular endothelial growth factor A; YBX1: Y-box binding protein 1; ZEB1: Zinc finger E-box binding homeobox 1.

Proliferation, metastasis, and apoptosis angiogenesis

Early studies revealed that the TUG1 promoter contains several binding sites for specificity protein 1 (Sp1), a transcription factor that regulates numerous key factors in cancer progression[88]. Through direct binding, Sp1 enhances TUG1 transcription, contributing to TUG1 overexpression. Functionally, TUG1 interacts with the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and suppressor of zeste 12 (SUZ12) to epigenetically silence the Krüppel-like factor 2 (KLF2) gene, thereby inhibiting apoptosis and promoting HCC cell proliferation and metastasis[68]. KLF2 itself has been demonstrated to suppress the growth and tumorigenesis of HCC through modulating the hedgehog (Hh) signaling pathway[89]. Interestingly, triiodothyronine (T3) and its receptor interaction have been shown to negatively regulate TUG1 expression by partially counteracting Sp1 activation[69]. T3 treatment also reduces the protein expression of EZH2, SUZ12, and cell cycle markers such as proliferating cell nuclear antigen and cyclin E in HCC cells, inhibiting proliferation and enhancing apoptosis[69]. Furthermore, TUG1 expression is positively correlated with alpha-fetoprotein (AFP), a key HCC biomarker, which is also downregulated by T3 treatment[69].

In addition to these mechanisms, TUG1 also regulates HCC progression through the modulation of diverse signaling pathways. For example, reactive oxygen species (ROS) modulator 1 (ROMO1) has been described as a key modulator of ROS, which contribute to HCC invasiveness[90]. Through interaction with upstream stimulatory factor 1 (USF1), TUG1 facilitates its recruitment to the ROMO1 promoter, thereby facilitating HCC cell proliferation and invasion[70]. TUG1 also contributes to tumor angiogenesis via dysregulation of vascular endothelial growth factor A (VEGFA), a central regulator of neovascularization involved in the progression of tumors, including HCC[91]. In hepatoblastoma (HB), TUG1 upregulation promotes tumor growth and hypervascularity by acting as a sponge for miR-34a-5p, thereby relieving the repression of VEGFA expression[71]. Furthermore, TUG1 has been linked to the activation of the Hh signaling pathway, which regulates diverse cellular processes, including carcinogenesis, and is activated by the interaction of sonic Hh (Shh) with the receptor protein patched homolog 1 or 2[92]. In HCC cells, TUG1 enhances Shh protein expression by alleviating the binding of miR-132 to Shh, which accelerates HCC progression and inhibits apoptosis[72]. Additionally, a previous study revealed a positive correlation between TUG1 overexpression and the expression of aurora kinase A (AURKA), potentially facilitating increased HCC proliferation, migration, invasion, and resistance to apoptosis[73]. Further investigation revealed that AURKA-overexpressing HCC cells presented increased epithelial-mesenchymal transition (EMT) and enhanced cancer stem cell (CSC) properties[93]. These effects were attenuated by the protein kinase B (AKT) inhibitor LY294002, suggesting that AURKA may regulate EMT and CSCs in HCC cells through the phosphatidylinositol 3-kinase (PI3K)/AKT pathway[93]. Consistently, silencing TUG1, which contains a miRNA response element (MRE) for miR-137, suppresses the expression of AKT2 and EMT-related genes [matrix metalloproteinase (MMP)-2 and MMP-9, and N-cadherin]. This thereby inhibits HCC proliferation and metastasis[74].

Beyond the PI3K/AKT pathway, TUG1 also regulates other oncogenic signaling networks in HCC. One such factor is zinc finger E-box binding homeobox 1 (ZEB1), whose aberrant expression is observed in various liver diseases[94]. Notably, ZEB1 facilitates HCC tumorigenesis by enhancing proliferation and invasion through the Wingless-Int (Wnt)/β-catenin signaling pathway[94]. Reduced expression of miR-142-3p has been closely associated with poor prognosis in HCC patients. These studies demonstrate the oncogenic function of TUG1, which sequesters miR-142-3p, a tumor suppressor that targets ZEB1, thereby facilitating HCC proliferation and EMT[75]. As a critical signaling axis, the Janus kinase (JAK)/signal transducer and activator of the transcription (STAT) signaling pathway plays a pivotal role in both normal and cancer cells[95]. Consequently, aberrant activation and dysregulation of the JAK/STAT pathway has been implicated in various diseases, including HCC[96]. TUG1, bearing MREs for miR-144[76] and miR-204-5p[77], facilitates deregulation of their downstream targets, which advances HCC progression. JAK2, which contains potential binding sites for miR-144 and miR-204-5p, is upregulated through TUG1's miRNA sponge activity, leading to increased proliferation, migration, angiogenesis, and tumorigenesis via activation of the JAK/STAT pathway[76,77].

In addition to its role in JAK/STAT signaling, TUG1 also contributes to HCC progression via the mammalian target of rapamycin (mTOR) pathway. As a crucial mediator of mTOR signaling, the overexpression of Ras related GTP binding D (RRAGD) has been implicated in driving aerobic glycolysis, enhancing the malignant features of HCC cells, and correlating with poor prognosis in HCC patients[97]. Elevated levels of phosphorylated mTOR and p70S6K have also been observed in HCC cells[78]. TUG1 promotes HCC progression by sequestering miR-144-3p, resulting in dysregulated RRAGD expression. This leads to increased proliferation, invasion, and resistance to apoptosis via hyperactivation of the mTOR/S6K pathway[78]. Distal-less homeobox 2 (DLX2), a critical regulator of the cell cycle, has been shown to increase HCC proliferation via the upregulation of cell cycle-related genes[98]. In the context of therapy resistance, elevated DLX2 levels are also associated with sorafenib resistance, which is correlated with a poorer prognosis in HCC patients[98]. Mechanistically, the knockdown of TUG1 relieves the suppression of miR-216b-5p, restoring the regulatory activity of DLX2, which suppresses growth and metastasis while sensitizing HCC cells to apoptosis[66]. Additionally, TUG1-mediated upregulation of interferon (IFN)-inducible transmembrane protein 3 (IFITM3) promotes HCC tumorigenesis by competitively binding to miR-29a. This effect is reversed upon the restoration of miR-29a expression achieved by TUG1 depletion[79]. Furthermore, IFITM3 levels are significantly elevated and associated with poor prognosis in HCC patients[99,100].

Apart from modulating a wide array of signaling cascades, TUG1 also facilitates HCC progression through the regulation of extracellular matrix (ECM) components. Collagen type I alpha 1 (COL1A1), a key factor in liver fibrosis[101], has been implicated as a biomarker for poor overall survival in HCC patients[102]. Notably, miR-29c-3p, which is inversely associated with both TUG1 and COL1A1 expression, can be restored upon TUG1 depletion, thereby reducing COL1A1 levels and suppressing HCC cell proliferation and motility[80]. Furthermore, TUG1 also regulates splicing factor expression. The serine/arginine-rich splicing factor (SRSF) family is aberrantly expressed in HCC, and elevated levels correlate with poor clinical outcomes[103]. Specifically, hypomethylation of the serine and arginine rich splicing factor 9 (SRSF9) promoter is linked to increased SRSF9 transcription, which contributes to the malignant behavior of HCC cells[104]. Further investigation into the oncogenic role of SRSF9 revealed that TUG1 acts as a miR-328-3p sponge, thereby alleviating the negative regulation of SRSF9 and driving the aggressive progression of HCC cells[65]. Additionally, TUG1-mediated downregulation of miR-1-3p has been shown to promote proliferation and inhibit apoptosis in HCC cells[81]. This activity likely results in increased expression of insulin like growth factor 1 (IGF1), a putative downstream target of miR-1-3p, which plays a key role in liver pathophysiology[81]. In support of this hypothesis, luciferase reporter assays conducted in colorectal cancer models have confirmed the interaction between miR-1-3p and IGF1, underscoring its broader relevance[105].

A study reported that the coexpression of the lncRNA HOXA transcript at the distal tip (HOTTIP) and TUG1 promotes HCC tumor growth by upregulating mucin 1 (MUC1)[82]. Notably, both lncRNAs harbor MREs for miR-4726-5p, suggesting that HOTTIP and TUG1 cooperatively alleviate the miR-4726-5p-mediated suppression of MUC1[82]. Combined treatment with sorafenib and solamargine reversed this effect, reducing the expression of MUC1, HOTTIP, and TUG1. Interestingly, silencing TUG1 significantly downregulated HOTTIP expression, whereas HOTTIP knockdown had no effect on TUG1 levels, suggesting that TUG1 may regulate other lncRNAs in HCC cells, potentially forming a complex regulatory network[82].

Immune response

As an immunologically privileged organ, the liver maintains a delicate balance between immunosuppression and immune activation to preserve physiological equilibrium. This balance is disrupted in HCC, where tumor cells acquire mutations that confer resistance to apoptosis and senescence, reprogram cellular metabolism, and modify the microenvironment, enabling evasion of host immune surveillance[106,107]. Emerging evidence highlights the involvement of lncRNAs, including HCC, in mediating cancer immunity[108,109]. In HB-associated HCC, TUG1 is notably elevated in HB-infected patients carrying beta-catenin mutations, a gene encoding β-catenin, which serves as a crucial regulator of the Wnt signaling pathway[83]. Additionally, TUG1 expression is positively correlated with C-X-C motif chemokine receptor 4 (CXCR4) expression[83], which is linked to poor prognosis in HCC patients and an increased presence of protumor immunocytes, including macrophages, neutrophils, and dendritic cells, as well as their respective biomarkers[110]. TUG1 appears to increase CXCR4 expression by competitively binding to miR-335-5p, underscoring its potential as both a biomarker and therapeutic target in immune-related HCC progression[83].

In addition to its association with CXCR4, TUG1 also contributes to broader HCC immune suppression. For example, TUG1 expression is positively correlated with sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15), a crucial immune suppressor that facilitates the migration of HCC cells[111]. A recent study further demonstrated that silencing TUG1 enhances T-cell activity and the production of cytokines, such as IFN-γ and interleukin (IL)-2, resulting in increased cytotoxicity in HCC cells, whereas TUG1 overexpression reverses these effects[84]. Mechanistically, TUG1 sponges miR-582-5p, a miRNA that negatively regulates Siglec-15, thereby upregulating Siglec-15 expression and suppressing T-cell-mediated responses[84]. Furthermore, TUG1 has been implicated in regulating the programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint axis, a key immunosuppressive pathway that enables tumors to evade immune detection and destruction[112]. Notably, PD-L1 is highly expressed on the surface, where it interacts with PD-1 on the surface of T cells, effectively suppressing their activation and proliferation and thus compromising host immune defenses against tumor cells[112,113]. In HCC patients, the expression pattern of TUG1 is positively correlated with that of PD-L1 and other immune checkpoint molecules [such as tumor necrosis factor (TNF) ligand superfamily member 4, cluster of differentiation (CD) 200, and CD274] and is closely associated with a poor prognosis[85]. Functional assays revealed that TUG1 knockdown significantly reduced the mRNA, protein, and phosphorylation levels of JAK2 and STAT3, whereas TUG1 overexpression partially restored PD-L1 levels[85]. Furthermore, treatment with a JAK2 inhibitor (AZ960) or a STAT3 inhibitor (A12232) also reduces the mRNA and protein levels of PD-L1, indicating that TUG1 may regulate PD-L1 expression through the JAK2/STAT3 pathway to modulate immune evasion in HCC[85].

Beyond transcriptional regulation, TUG1 also contributes to immune suppression through posttranscriptional modifications. The m⁶A RNA modification is the most abundant type of mRNA modification that regulates the biological fate of target mRNAs, influencing their cellular dynamics[114]. A key component of the m⁶A methyltransferase complex, methyltransferase-like 3 (METTL3), which normally functions as a “writer”, is closely related to the poor prognosis of HCC patients and enhances HCC tumorigenicity[115]. A study revealed a positive correlation between TUG1 and METTL3 in HCC patients, suggesting that METTL3-mediated m⁶A modification promotes TUG1 upregulation[86]. Consistently, METTL3 silencing suppressed TUG1 expression and reduced the m⁶A modification of TUG1 in HepG2 cells. Intriguingly, TUG1 knockdown in HCC livers increases the presence of M1-like macrophages and CD8⁺ and CD4⁺ T cells, which exhibit antitumor immunity with increased production of IFN-γ, IL-2, and TNF-α[86]. Further analysis revealed that TUG1 contains putative MREs for miR-141 and miR-340, which target PD-L1 and CD47, respectively[86]. CD47 is widely recognized as an antiphagocytic signal that tumor cells exploit to escape phagocytosis[116]. In addition, RNA structure analysis has identified potential docking sites for the transcription factor Y-box binding protein 1 (YBX1) within the TUG1 sequence, implicating it in transcriptional regulation[117]. YBX1 directly binds to the promoters of PD-L1 and CD47 to activate their transcription, a process that is significantly impaired upon TUG1 depletion due to reduced YBX1 recruitment[86]. Overall, this study demonstrated that TUG1 overexpression, potentially through m⁶A modification, enhances PD-L1 and CD47 expression by sequestering miR-141 and miR-340, respectively, thereby alleviating their negative regulation[86]. Furthermore, TUG1 facilitates YBX1 recruitment to the PD-L1 and CD47 promoters, driving their transcription and enhancing HCC immune evasion, tumor growth, and metastatic potential[86]. However, further investigations are warranted to clarify the extent to which METTL3 contributes to TUG1 regulation across different HCC contexts.

Glycolysis

The concept of cancer metabolism arises from the observation that diverse tumors often exhibit metabolic signatures distinct from those of noncancerous tissues[118]. These signatures influence the choice of therapies to match these metabolic profiles to maximize patients’ benefits[118]. Growing evidence indicates that lncRNAs act as crucial modulators of metabolic reprogramming in numerous cancers, including HCC[119,120]. The metabolic switch in cancer cells, first described by Warburg[121-123], is characterized by rerouting energy metabolism mainly to glycolysis despite the presence of sufficient oxygen, a phenomenon termed the “Warburg effect” or “aerobic glycolysis”. Along with increasing adenosine triphosphate (ATP) output, the buildup of glycolytic intermediates could be diverted into various biosynthetic pathways, thus enabling the production of essential building blocks for cell proliferation[124,125]. TUG1 was revealed to promote methylation (H3K27me3) of the cyclin-dependent kinase inhibitor 1A (p21) promoter, an antiproliferative modulator[126], through direct interaction with EZH2 of PRC2[87]. TUG1-mediated disruption of p21 enhances the binding of the transcription factor E2F transcription factor 1, which was previously demonstrated to be the target of p21 regulation[127], to the miR-445-3p promoter region[87]. Notably, miR-445-3p was markedly diminished in TUG1-knockdown HCC cells. In line with earlier observations, depletion of miR-445-3p led to increased migration, invasion, cell proliferation, and glycolysis, whereas its overexpression in TUG1-knockdown cells reversed these effects, supporting its tumor-promoting role in HCC[87]. Further investigation revealed that AMP-activated protein kinase beta 2 (AMPKβ2), a well-characterized metabolic tumor suppressor[128], contains a putative binding site for miR-445-3p, indicating that AMPKβ2 is suppressed by TUG1-mediated upregulation of miR-445-3p in HCC[87]. Compared with their less metastatic counterparts, metastatic HCC cells exhibit higher levels of hexokinase 2 (HK2), phosphorylated mTOR, and glycolysis[87]. This observation suggests an association between HCC metastasis and increased glycolysis.

In addition to its role in intrinsic tumor regulation, TUG1 also participates in shaping the tumor microenvironment (TME). Emerging evidence highlights the essential role of cancer-associated fibroblasts (CAFs) as key players in tumor development, nurturing the TME through the secretion of ECM components, growth factors, chemokines, and exosomal miRNAs[129,130]. HCC cells supplemented with CAF-derived exosomes exhibit increased migration, invasion (increased MMP-2 and MMP-9), and glycolysis [increased HK2 and lactate dehydrogenase (LDHA)]. LncRNA profiling of CAF-derived exosomes revealed that TUG1 was highly expressed compared with other elevated lncRNAs (NEAT1, H19, and MALAT1)[67]. Bioinformatics analysis further indicated that TUG1 harbors a potential binding site for miR-524-5p, suggesting that TUG1 sequesters miR-524-5p, thereby diminishing its regulatory influence[67]. Notably, miR-524-5p directly targets the 3’ UTR of SIX homeobox 1 (SIX1), an oncogene implicated in various types of tumors[131,132], thereby promoting HCC development via SIX1 upregulation[67]. Indeed, a recent study suggested that SIX1 is a key transcription factor that directly induces the expression of many glycolytic genes and promotes the Warburg effect in cancer cells[133]. Taken together, these findings highlight the critical role of the TME in HCC progression and suggest that TUG1 is a crucial glycolysis-regulated lncRNA.

THE INVOLVEMENT OF THE TUG1 REGULATORY MECHANISM IN NONCANCEROUS LIVER DISEASES

HCC commonly arises from noncancerous liver diseases. Given the potent regulatory role of TUG1, it may influence fibrosis, cirrhosis, liver injury, and MASLD. Since cirrhosis frequently transitions into HCC, investigating the role of TUG1 in early liver pathologies is vital for developing preventive and therapeutic strategies. Table 2 presents the molecular mechanisms and associated target genes of TUG1[134-140]. Figure 3 depicts its regulatory interactions in various liver diseases.

Figure 3 Taurine-upregulated gene 1's involvement in liver pathology. This diagram illustrates the multifaceted role of taurine-upregulated gene 1 (TUG1) in liver injury, fibrosis/cirrhosis, and metabolic dysfunction–associated steatotic liver disease (MASLD). TUG1 interacts with various molecules, including microRNAs (miRNAs) (miR-140-5p, miR-29b, miR-194, miR-1934-3p, miR-142-3p), proteins [tumor necrosis factor (TNF)-α, collagen type I alpha 1 (COL1A1), sirtuin 1 (SIRT1), selenoprotein F, pyruvate dehydrogenase kinase 4 (PDK4), autophagy protein 5 (ATG5)], and cellular processes, contributing to the progression of liver diseases. In liver injury, TUG1 is shown to influence TNF-α signaling and SIRT1 activity. In liver fibrosis/cirrhosis, TUG1 affects the expression of COL1A1. In MASLD, TUG1 modulates the expression of PDK4 and ATG5, which are key players in metabolic pathways. T-bars indicate repression, and arrows indicate activation or positive regulation (created in BioRender). ATG5: Autophagy protein 5; COL1A1: Collagen type I alpha 1; MASLD: Metabolic dysfunction–associated steatotic liver disease; MiRNAs: MicroRNAs; PDK4: Pyruvate dehydrogenase kinase 4; SelenoF: Selenoprotein F; SIRT1: Sirtuin 1; TNF-α: Tumor necrosis factor alpha; TUG1: Taurine upregulated gene 1.

Table 2 The regulatory axis of taurine upregulated gene 1 in non-cancerous liver disease.

Function	Target miRNA	Target protein	Molecular mechanism	TUG1 role	Ref.
Liver injury
-	-	-	Overexpression of TUG1 suppresses endoplasmic reticulum stress, reduces apoptosis, and upregulates anti-apoptotic proteins	Cryoprotective	Su et al[134]
MiRNA sponge/ceRNA	MiR-194	SIRT1	TUG1 sequesters miR-194, a negative regulator of SIRT1	Anti-apoptotic, anti-inflammatory	Gu et al[135]
MiRNA sponge/ceRNA	MiR-140-5p	TNF	TUG1 sequesters miR-140-5p, a negative regulator of TNF-α	Pro-apoptotic, pro-inflammatory	Liu et al[136]
Liver fibrosis/cirrhosis
-	MiR-29b	COL1A1/α-SMA	Overexpression of TUG1 is positively correlated with expression of COL1A1 and α-SMA while negatively correlated with miR-29b	Pro-fibrotic	Han et al[137]
-	-	PDK4	Overexpression of TUG1 is positively correlated with expression of PDK4	Anti-ferroptotic	Zhang et al[138]
MiRNA sponge/ceRNA	MiR-142-3p	ATG5	TUG1 sequesters miR-142-3p, a negative regulator of ATG5	Pro-autophagic endothelial-mesenchymal transition-promoting	Zhang et al[139]
Metabolic dysfunction–associated steatotic liver disease
MiRNA sponge/ceRNA	MiR-1934-3p	SelenoF	TUG1 sequesters miR-1934-3p, a negative regulator of SelenoF	Glucose-lipid metabolism regulator	Wang et al[140]

A-SMA: Alpha-smooth muscle actin; ATG5: Autophagy protein 5; CeRNA: Competitive endogenous RNA; COL1A1: Collagen type I alpha 1; MiRNAs: MicroRNAs; PDK4: Pyruvate dehydrogenase kinase 4; SelenoF: Selenoprotein F; SIRT1: Sirtuin 1; TNF: Tumor necrosis factor; TUG1: Taurine upregulated gene 1.

Liver injury

One of the most remarkable aspects of the liver is its extraordinary ability to regenerate following injury. As the center of metabolic homeostasis and a critical signaling hub, the liver regulates essential metabolic processes, including glucose, lipid, and amino acid metabolism[141,142]. Liver diseases vary widely but are generally characterized by hepatocyte damage, immune cell infiltration, and activation of hepatic stellate cells (HSCs), all of which compromise liver function and structure[141,142]. The development of these conditions is influenced by several factors, including hepatotropic viral infections, drug-induced liver injury, chronic alcohol abuse, hepatitis B virus and hepatitis C virus infections, and MASLD[142,143]. Interestingly, certain lncRNAs, such as Gm²199[144], Mir122hg[145], and Airn[146], which play protective roles against liver damage[147], have been implicated as key regulators of liver injury.

TUG1 has emerged as a potent modulator of liver injury responses. During liver preservation for transplantation, cold ischemia–reperfusion injury is induced by cold-induced damage to hepatic sinusoidal endothelial cells and microvascular dysfunction, significantly compromising transplant viability[148]. LncRNA profiling revealed a 6-fold downregulation of TUG1 in cold-injured mouse livers. Lentivirus-mediated TUG1 overexpression inhibited the endoplasmic reticulum (ER) stress pathway, alleviated cold-induced apoptosis, and increased antiapoptotic protein levels in cold-stressed hepatocytes and liver sinusoidal endothelial cells (LSECs). In vivo, TUG1 exerts protective effects, reducing the levels of hepatic injury markers (alanine aminotransferase, aspartate aminotransferase, LDHA, and glutamate dehydrogenase) and inflammatory cytokines. Furthermore, preinjection of mice with Lenti-TUG1 resulted in prolonged hepatic graft survival compared with that of controls[134]. Dexmedetomidine (DEX), a potent and selective α2-adrenergic agonist used for clinical anesthesia, can alleviate local and systemic inflammation and has been shown to reduce the severity of hepatic injury[149,150]. DEX treatment ameliorated oxygen and glucose deprivation (OGD)-induced hepatocyte injury, suppressed apoptosis, and enhanced cell viability, which correlated with increased TUG1 and sirtuin 1 (SIRT1) expression[135]. SIRT1, a histone deacetylase, exerts hepatoprotective effects by mitigating inflammation and liver injury[151,152]. Bioinformatics analysis identified miR-194 as a predicted TUG1 target, which also contains a putative SIRT1 binding site. Notably, depletion of TUG1 or introduction of a miR-194 mimic abolished the protective effect of DEX on the apoptosis of OGD-treated cells, which was partially rescued by miR-194 inhibition or SIRT1 overexpression[135]. Collectively, these studies demonstrate that TUG1 exerts its protective effects through multiple mechanisms, including the inhibition of ER stress, apoptosis, and inflammation, suggesting a complex interplay between TUG1 and various signaling pathways in liver injury, highlighting its potential as a therapeutic target for improving liver transplantation outcomes.

Conversely, TUG1 has also been shown to promote liver injury. Previous investigations demonstrated TUG1 upregulation in liver tissues following lipopolysaccharide (LPS) treatment, suggesting its involvement in LPS-induced hepatocyte injury[136]. TUG1 silencing significantly reduces hepatocyte damage and inflammatory infiltration[136]. Moreover, miR-140-5p was later identified as a direct target of TUG1, which negatively regulates TNF, a key proinflammatory cytokine[153,154]. In support of the role of TUG1 in miR-140-5p suppression, the overexpression of TUG1, TNF, or miR-140-5p increased the levels of apoptosis (B-cell lymphoma 2 associated X protein, caspase-3), inflammation (TNF, IL-6), and ROS[136]. These effects were partially mitigated by TUG1 or TNF silencing or miR-140-5p mimic overexpression[136]. Although evidence supports the hepatoprotective role of TUG1, some findings suggest that its function may vary depending on the molecular mechanisms underlying different causes of injury.

Liver fibrosis/cirrhosis

Liver fibrosis is defined by the pathological accumulation of ECM initiated by repeated repair processes following hepatic injury[155]. Under normal conditions, the liver exhibits astonishing regenerative abilities, partly through HSCs[156]. Upon activation, these subpopulation cell types undergo transdifferentiation into hepatic collagen-producing myofibroblasts, forming a regulated fibrous scar[157]. Generally, this process is transient and is counteracted by antifibrotic pathways[157,158]. However, with prolonged liver injury, the balance between profibrogenic and antifibrotic mechanisms is disrupted, resulting in pathological production of the ECM and the onset of progressive liver problems[157,158]. Investigations using liver fibrosis model mice revealed a positive correlation between TUG1 and key fibrotic markers, including COL1A1, alpha-smooth muscle actin (α-SMA), MMP-2, MMP-9, MMP-10, and tissue inhibitor matrix metalloproteinase 1[137]. Upon treatment with transforming growth factor-β, which plays a central pathogenic role in fibrosis across multiple organs[159-161], these fibrotic markers are significantly elevated and reverse the effect of TUG1 knockdown in HSCs[137]. In contrast, the overexpression of TUG1 in primary murine HSCs increased the expression of these fibrotic markers, whereas the introduction of a miR-29b mimic, a miRNA that was previously implicated in liver fibrosis[162], attenuated the effects of TUG1 overexpression[137]. These findings suggest that TUG1 might modulate fibrogenesis via miR-29b and fibrotic pathways. However, whether miR-29b directly controls the expression of fibrotic genes remains to be explored.

In addition to direct regulation of fibrotic pathways, TUG1 has been shown to modulate HSC ferroptosis, a promising strategy for clearance of liver fibrosis via drug-induced ferroptosis[163,164]. Notably, pyruvate dehydrogenase kinase 4 (PDK4), a critical glycolytic regulator, facilitates ferroptosis resistance by inhibiting pyruvate dehydrogenase-dependent pyruvate oxidation[165]. Depletion of TUG1 diminishes PDK4 expression without affecting other PDK isoforms. Consequently, glycolytic activity and genes (HK2, pyruvate kinase muscle isozyme M2, and LDHA) and ferroptosis [solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4] are also downregulated in TUG1-knockdown HSCs[138,165]. Conversely, overexpressing PDK4 in TUG1-depleted HSCs partially restores glycolytic gene expression, indicating that TUG1 modulates cellular energy metabolism and susceptibility to ferroptosis in HSCs[138]. In line with these observations, studies have shown that TUG1 also facilitates fibrotic progression in pulmonary fibrosis[166] and renal tubular fibrosis[167], supporting its profibrotic activity. Therefore, further research is warranted to fully elucidate the intricate mechanisms by which TUG1 contributes to the progression of organ fibrosis and to explore its potential as a therapeutic target.

Cirrhosis is an advanced stage of liver fibrosis marked by the activation of profibrogenic phenotypes in various cell types. The event restricts blood flow, thereby compromising the overall liver’s function and metabolic activities and potentially triggering portal hypertension as a compensatory response[168]. Under normal conditions, LSECs form a barrier between the blood and liver parenchyma and maintain the quiescence of HSCs[157,169]. However, liver damage induces LSEC capillarization, which is characterized by the loss of their native function[157,169]. Consequently, these capillarized LSECs fail to suppress HSC activation, driving the progression of liver fibrosis and cirrhosis[157,169]. LPS from gram-negative bacteria, commonly known as a driver of sepsis, has been implicated in the gut-liver axis in the development and progression of chronic liver diseases[170,171]. Impaired autophagy and endothelial-mesenchymal transition (EndMT) in LSECs have been linked to liver cirrhosis[172,173]. Among the lncRNAs identified to be upregulated following LPS treatment, TUG1 exhibited the strongest dose-dependent expression in starved LSECs. Further analysis revealed the putative binding site for miR-142-3p on autophagy protein 5 (ATG5), a key autophagy-related gene[172], and TUG1[139]. Notably, the overexpression of miR-142-3p lowered ATG5 levels, inhibited migration, and subsequently suppressed EndMT-related genes (light chain 3B and α-SMA) and autophagic markers (P62, VE-cadherin, and CD31)[139]. Collectively, these findings demonstrate that TUG1 directly targets miR-142-3p through sponging activity, thereby impairing ATG5 regulation to promote LSEC EndMT and autophagy. These findings offer perspectives on TUG1-based therapeutic strategies for liver fibrosis and cirrhosis. Interestingly, TUG1 appears to play a profibrotic role in both LSECs and HSCs, albeit through different mechanisms, suggesting that a synergistic approach targeting TUG1 in both cell types could be a promising antifibrotic strategy.

MASLD

MASLD, formerly known as nonalcoholic fatty liver disease, is a steatotic liver disease that develops alongside cardiometabolic risk factors without excessive alcohol intake[174]. As the primary cause of chronic liver disease, MASLD is strongly associated with obesity, cardiovascular risk, kidney disease, liver failure, and liver cancer[175]. Recent findings highlight the regulatory role of the long noncoding RNA TUG1 in hepatic steatosis. Specifically, the TUG1/miR-1934-3p/selenoprotein F (SelenoF) axis was demonstrated to be a key regulator of hepatocyte steatosis induced by sodium palmitate[140]. SelenoF, an ER-resident protein, is crucial for lipid and glucose metabolism and significantly accelerates energy metabolism[176,177]. These findings suggest that TUG1 acts as a ceRNA, influencing hepatic metabolism through miR-1934-3p, SelenoF, and the insulin receptor substract 1/AKT signaling pathway, highlighting TUG1 as a potent therapeutic target for MASLD treatment[140]. Although this study indicates that TUG1 plays a protective role against MASLD, more studies are warranted to confirm and elucidate the molecular mechanisms involved.

Nevertheless, owing to the multifactorial nature of MASLD, including its links to genetic susceptibility and insulin resistance, further investigation is needed. Notably, insulin-resistant states may increase lipogenesis, increase lipotoxic intermediates, and exacerbate metabolic imbalances[178]. TUG1 has been identified as a regulatory lncRNA capable of mitigating inflammation and improving insulin sensitivity in the adipose tissues of obese mice[179]. This function appears to be mediated by sponging miR-204, which targets SIRT1. TUG1 overexpression leads to derepression of SIRT1, thereby promoting anti-inflammatory signaling through glucose transporter 4, peroxisome proliferator-activated receptor gamma (PPAR-γ), and AKT[179]. Additionally, TUG1 has been associated with gestational diabetes mellitus. Through competitive binding with miR-328-3p, which targets sterol regulatory element binding protein (SREBP)-2 and activates extracellular signal-regulated kinase (ERK) signaling, TUG1 appears to mitigate insulin resistance via suppression of the SREBP-2/ERK axis[180]. Collectively, these findings suggest that TUG1 contributes to insulin regulation during the early stages of metabolic dysfunction and may serve as a preventive target in MASLD development.

In a clinical study, reduced TUG1 levels were observed in the adipose tissues of obese women, with positive correlations with body mass index, waist and hip circumference, insulin levels, and the mRNA levels of key lipogenic transcription factors such as PPAR-γ, PGC1-α, SREBP-1c, fatty acid synthase, and acetyl-CoA carboxylase[181]. However, such correlations were not observed in larger cohort studies, particularly with obesity indices, suggesting potential context-dependent regulation[182,183]. These inconsistencies underscore the importance of additional mechanistic studies to fully define the contribution of TUG1 to lipid metabolic pathways.

CONCLUSION

LncRNAs have emerged as key regulators of gene expression and biological pathways, significantly contributing to human diseases and cancer progression through various molecular mechanisms. TUG1 has been widely recognized for its role in HCC, primarily facilitating HCC progression by functioning as a ceRNA and competitively binding to tumor-suppressing miRNAs, thereby upregulating oncogenic proteins and driving multiple cancer hallmarks. While the ceRNA model of TUG1 is well supported, comprehensively defining TUG1’s function within specific regulatory axes requires consideration of factors such as ceRNA and miRNA abundance, stoichiometry, the number of shared MREs, and potential indirect interactions[184,185]. Moreover, large-scale patient datasets demonstrating an inverse correlation between TUG1 and its target miRNAs would significantly strengthen its functional validation beyond in vitro studies[184,185]. Apart from its ceRNA function, TUG1 directly interacts with chromatin regulators (e.g., PRC2, EZH2) and transcription factors (e.g., USF1, YBX1), playing a broader role in gene regulation. Given its multifaceted molecular mechanisms, interpreting TUG1’s function on the basis of a single molecular function risks oversimplifying its broader impact in HCC and other disease settings.

In addition to TUG1, a multitude of other ncRNAs, including miRNAs and circular RNAs (circRNAs), have emerged as crucial players in liver diseases[186-190]. These ncRNAs form intricate regulatory networks that interact with each other and with protein-coding genes to influence various cellular processes, such as inflammation, fibrosis, regeneration, and carcinogenesis[191-194]. For example, miRNAs can directly target mRNAs to suppress their translation, whereas circRNAs can act as sponges for miRNAs, modulating their activity[195,196]. These interactions are not limited to the miRNA-mRNA or circRNA-miRNA axes. Notably, lncRNAs and circRNAs can compete for common miRNAs. A bioinformatics-constructed ceRNA network revealed 38 circRNA/miRNA/mRNA axes (7 circRNAs, 8 miRNAs, and 20 mRNAs) and 436 lncRNA/miRNA/mRNA axes (104 lncRNAs, the same 8 miRNAs, and 20 mRNAs). These 20 key differentially expressed mRNAs are targeted by both circRNA and lncRNA axes in HCC, suggesting a more intricate and cooperative mechanism of gene regulation[197]. Understanding the interplay between different ncRNA classes and TUG1 is crucial for deciphering the complex molecular mechanisms underlying liver diseases and for identifying potential therapeutic targets.

Emerging evidence suggests that ncRNAs can also communicate between different cell types within the liver microenvironment, contributing to disease progression[198-200]. For example, ncRNAs can be packaged into exosomes and transported from one cell to another, influencing recipient cell behavior[201,202]. This intercellular communication mediated by ncRNAs adds another layer of complexity to the pathogenesis of liver diseases. Further research is needed to fully elucidate the roles of various ncRNAs and their interactions in different liver diseases, paving the way for the development of novel therapeutic strategies that target these ncRNA networks. Notably, in addition to their established roles in miRNA sponging, recent bioinformatic analyses have identified protein docking sites on TUG1, suggesting that TUG1 directly interacts with transcription factors that may drive HCC progression. These findings emphasize the importance of exploring non-ceRNA mechanisms to fully elucidate the multifaceted functions of TUG1 in liver diseases.

Given that lncRNAs, including TUG1, often exhibit cell type-specific expression patterns, emerging transcriptomic tools such as single-cell RNA sequencing (scRNA-seq) provide promising avenues for exploring their functional roles in heterogeneous tissues such as the liver. Recent advances, such as the ELATUS framework, have optimized lncRNA detection, improving the sensitivity and specificity of scRNA-seq analysis[203]. Leveraging these technologies may help delineate the cell-specific roles of TUG1 and reveal novel regulatory pathways involved in liver pathologies, potentially guiding the development of targeted treatments.

On the basis of the evidence presented in this review, TUG1 has potential as a diagnostic biomarker for HCC. Analyses using large-scale liver HCC (LIHC) datasets such as The Cancer Genome Atlas datasets revealed an inverse correlation between TUG1 and its target miRNAs, which is consistent with its function as a ceRNA. Conversely, TUG1 expression is positively correlated with oncogenic targets negatively regulated by miRNAs, including AFP, ROMO1, AKT2, ZEB1, SRSF9, CXCR4, Siglec-15, PD-L1, CD47, METTL3, and SIX1. Additionally, elevated TUG1 expression has been associated with poorer prognostic outcomes in LIHC patients. These findings suggest that predictive models incorporating TUG1, its miRNA partners, and downstream targets may serve as powerful tools for HCC diagnosis and prognosis.

In the context of HCC, the role of TUG1 in mediating chemoresistance remains insufficiently characterized. Existing evidence suggests that TUG1 expression is significantly upregulated in adriamycin-resistant HCC tissues[204]. Functional silencing of TUG1 has been shown to sensitize cells to adriamycin by promoting apoptosis and repressing the expression of multidrug resistance-associated genes, notably P-glycoprotein and ATP-binding cassette subfamily B member 1 (also known as MDR1)[204]. Similar regulatory roles of TUG1 in modulating drug resistance have been identified in other cancers, including paclitaxel resistance in ovarian cancer[205], 5-fluorouracil resistance in colorectal cancer[206], and cisplatin/adriamycin/etoposide resistance in small cell lung cancer[207]. Despite these observations, conflicting reports from cervical cancer[208] and glioma[209] studies suggest a potential antiresistance role for TUG1, highlighting a possible tissue-specific context for its function. Importantly, studies evaluating the role of TUG1 in resistance to sorafenib, the standard treatment for advanced HCC, are lacking[210]. Notably, only one study reported that solamargine, either alone or in combination with sorafenib, reduces TUG1 expression in vivo in HCC models[82]. Additional investigations are necessary to clarify whether TUG1 is a consistent modulator of drug sensitivity and resistance in HCC.

Owing to their potential for precision targeting, lncRNA-based therapies are gaining attention[211]. Unlike mRNAs, lncRNAs are typically expressed at lower levels and with greater specificity. Even when they vary between individual cells rather than being universally expressed at low levels, lncRNAs exhibit greater cell-type specificity than protein-coding genes do[212]. Interestingly, even ubiquitously expressed lncRNAs may have cell-type-specific functions, suggesting new therapeutic avenues[212]. Therapeutic targeting of tumor-promoting lncRNAs such as TUG1 can be achieved through antisense oligonucleotides, short interfering RNAs, or small molecules, while genome-editing platforms such as clustered regularly interspaced short palindromic repeat interference offer transcriptional silencing capabilities[212]. Clinical trials exploiting lncRNA promoter specificity, such as BC-819 targeting H19, highlight the feasibility of using lncRNAs as vectors for delivering cytotoxic genes to specific tumor tissues[36,213]. Overcoming challenges related to specificity, delivery, and tolerability will be key to realizing the full potential of lncRNA-based therapeutics[211]. On the basis of this review, TUG1 has emerged as a promising target for the treatment of liver cancer and liver disease, showing potential for prevention and early management. Interestingly, TUG1 has been implicated in cancer chemoresistance. However, further investigation into the broader molecular functions of TUG1 is essential to validate its accuracy and effectiveness as a novel therapeutic target in clinical applications.

ACKNOWLEDGEMENTS

We would like to thank all members of the Center of Excellence in Hepatitis and Liver Cancer and STAR for Anti-fibrosis Therapeutics and Mechanisms, Faculty of Medicine, Chulalongkorn University, for constructive feedback in writing this review.