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

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.

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.