潜在抗肝纤维化药物与靶点相关信号通路研究进展

周鑫; 王智; 何雪茹; 付裕豪; 荀雪姣; 李颖; 董占军

doi:10.3969/j.issn.1001-5256.2023.12.027

潜在抗肝纤维化药物与靶点相关信号通路研究进展

DOI: 10.3969/j.issn.1001-5256.2023.12.027

周鑫^{1, 2},
王智^{1, 2},
何雪茹^{1, 2},
付裕豪^{1, 2},
荀雪姣^{1, 2},
李颖²,
董占军^2, , ,

1.
河北医科大学研究生学院，石家庄 050017
2.
河北省人民医院药学部，石家庄 050057

基金项目:

河北省卫健委课题 (20210037)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：周鑫负责文献检索，撰写论文；王智、何雪茹、付裕豪、荀雪姣负责资料分析；李颖、董占军负责指导撰写文章并最终定稿。

详细信息

通信作者:
董占军， 13313213656@126.com （ORCID： 0000-0001-5349-4970）

计量
- 文章访问数: 335
- HTML全文浏览量: 234
- PDF下载量: 64
- 被引次数: 0
出版历程
- 收稿日期: 2023-03-13
- 录用日期: 2023-05-09
- 出版日期: 2023-12-12

Research advances in signaling pathways associated with potential anti-liver fibrosis drugs and targets

Xin ZHOU^{1, 2},
Zhi WANG^{1, 2},
Xueru HE^{1, 2},
Yuhao FU^{1, 2},
Xuejiao XUN^{1, 2},
Ying LI²,
Zhanjun DONG^{2
, ,
,}

1.
Graduate School of Hebei Medical University，Shijiazhuang 050017，China
2.
Department of Pharmacy，Hebei General Hospital，Shijiazhuang 050057，China

Research funding:

Project of Health Commission of Hebei Province (20210037)

More Information

Corresponding author: DONG Zhanjun， 13313213656@126.com （ORCID： 0000-0001-5349-4970）

摘要

摘要: 肝纤维化是慢性肝病进展为肝硬化甚至肝癌的关键一步。近年来，大量研究表明了干预肝纤维化进程的必要性，各种抗肝纤维化药物及活性成分相继被发现。非编码RNA在调解肝纤维化进程中也发挥重要作用，寻找能够调节信号通路介导的上游非编码RNA可以为抗肝纤维化治疗提供新的见解。本文分别介绍了TGF-β、Wnt/β-catenin、PI3K/Akt/mTOR、NF-κB、Hippo和MAPK信号通路介导的肝纤维化进程，并列举了各信号通路中最新的抗肝纤维化药物或活性成分以及相关非编码RNA介导的抗肝纤维化靶点与药物的研究进展，以期为抗肝纤维化提供新的研究思路和治疗方法。
- 肝纤维化 /
- 信号传导 /
- 药用制剂 /
- RNA，未翻译
Abstract: Liver fibrosis is a key step in the progression of chronic liver diseases to liver cirrhosis and even liver cancer. In recent years， a large number of studies have shown the necessity of intervening in the process of liver fibrosis， and various anti-liver fibrosis drugs and active ingredients have been discovered. Non-coding RNAs also play an important role in the process of liver fibrosis， and searching for upstream non-coding RNAs that can regulate signaling pathways can provide new insights for anti-liver fibrosis treatment. This article introduces the process of liver fibrosis mediated by the TGF-β， Wnt/β-catenin， PI3K/Akt/mTOR， NF-κβ， Hippo， and MAPK signaling pathways， lists the latest anti-liver fibrosis drugs or active components in each signaling pathway， and summarizes the research advances in anti-liver fibrosis targets and drugs mediated by related non-coding RNAs， so as to provide new research ideas and treatment methods for anti-liver fibrosis treatment.
- Hepatic Fibrosis /
- Signal Transduction /
- Pharmaceutical Preparations /
- RNA， Untranslated

HTML全文

图 1 肝纤维化信号传导通路

Figure 1. Diagram of signal transduction pathways in liver fibrosis

下载: 全尺寸图片幻灯片

表 1 抗肝纤维化活性成分及潜在药物与相关信号通路与试验剂量和类型总结

Table 1. Summary of anti-hepatic fibrosis active ingredients and potential drugs with related signaling pathways and trial dosages and types

抗肝纤维化活性成分/潜在药物	相关信号通路	试验剂量	试验类型
柚木叶提取物^［7］	TGF-β/SMAD2/7	50、100、200 mg/kg	CCl₄诱导的小鼠肝纤维化模型
芝麻酚^［8］	TGF-β/SMAD3/7	50、100 mg/kg	TAA诱导的大鼠肝纤维化模型
阿司匹林^［9］	TGF-β/SMAD2/3	10、20、40 mmol/L和30 mg/kg	HSC-T6，TAA诱导的大鼠肝纤维化模型
柠檬素^［10］	TGF-β/SMAD2/3/7	5、15 μmol/L和10、20 mg/kg	HSC-LX2，小鼠AML-12，CCl₄诱导的小鼠肝纤维化模型
咖啡因^［12］	TGF-β/SMAD3和MAPK	50 mg/kg	TAA诱导的大鼠肝纤维化模型
		50 mg/kg	高胆固醇饮食诱导的实验性非酒精性脂肪性肝炎大鼠模型
RBO^［13］	TGF-β1/FAK和NF-κβ	0.2、0.4 mL/kg	TAA诱导的大鼠肝纤维化模型
五味子酯甲^［14］	TGF-β1/TAK1/MAPK和NF-κB	5 μmol/L和1、2、4 mg/kg	HSC-T6，TAA诱导的小鼠肝纤维化模型
漆黄素^［16］	Wnt3a/β-catenin	50、100 mg/kg	TAA诱导的大鼠肝纤维化模型
HNK^［17］	Wnt3a/β-catenin	12.5、25、50 μmol/L	HSC-LX2，HSC-T6，HepG2癌细胞
多沙唑嗪^［20］	PI3K/Akt/mTOR	1、2、5、10、15 μmol/L	HSC-LX2
		2.5、5、10 mg/kg	CCl₄诱导的小鼠肝纤维化模型
富马酸替诺福韦二吡呋酯^［21］	PI3K/Akt/mTOR	100、200 μmol/L	HSC-LX2，HSC-T6，HepG2细胞
		100 mg/kg	TAA诱导的小鼠肝纤维化模型
委陵菜酸^［22］	PI3K/Akt/mTOR和NF-κB	1.5、3.0 mg/kg	CCl₄诱导的大鼠肝纤维化模型
二氢杨梅素^［25］	PI3K/Akt和NF-κB	20、40 mg/kg	TAA诱导的小鼠肝纤维化模型
甲氧基丁香酚^［26］	NF-kB	15、30、60、125、250 μmol/L	HSC-LX2，HSC-GRX
		0.25、1 mg/kg	CCl₄诱导的小鼠肝纤维化模型
獐牙菜提取物^［27］	NF-κB和TGF-β/SMAD2/3	100、200、400 mg/kg	CCl₄诱导的大鼠肝纤维化模型
西他列汀^［28］	Nrf2/NF-κB	10 mg/kg	Con A诱导的肝炎相关肝纤维化小鼠模型
白藜芦醇^［30］	Hippo	60 μmol/L和20 mg/kg	HSC-LX2，CCl₄诱导的小鼠肝纤维化模型
L-NAT^［31］	Hippo/YAP1和TGF-β1/SMAD	2.5、5 mg/kg	CCl₄诱导的小鼠肝纤维化模型
香芹酚^［33］	MAPK	25、50、100 mg/kg	HSC-T6细胞，CCl₄诱导的小鼠肝纤维化模型
HNK^［34］	p38 MAPK和TGF-β1/SMAD2/3	10、20、30 μmol/L和10 mg/kg	HSC-LX2，CCl₄诱导的小鼠肝纤维化模型

下载: 导出CSV

表 2 ncRNA及药物与肝纤维化相关通路与试验类型总结

Table 2. Summary of non-coding RNAs and drug and liver fibrosis-related pathways and trial types

ncRNA/药物	相关信号通路/分子	作用靶点	试验类型
miRNA
miR-139-5p^［36］	TGF-β	PMP22	CCl₄诱导的小鼠肝纤维化模型
miR-137-3p^［37］	TGF-β	Ppic	CCl₄诱导的小鼠肝纤维化模型
miR-497^［38］	TGF-β/SMAD	SMAD7	HSC-LX2
miR-34a-5p^［39］	TGF-β1/SMAD4	lncRNA CCAT2	HSC-LX2，HBV肝纤维化患者及健康人群
miR-6766-3p^［40］	TGF-β2/SMAD	TGF-β2	HSC-LX2，CCl₄诱导的小鼠肝纤维化模型
miR-130b‐5p^［41］	AMPK/TGF-β/SMAD2/3	SIRT4	HSC-T6，CCl₄诱导的小鼠肝纤维化模型，纤维化或其他肝脏疾病患者
miR-124^［42］	NF-κB	IQGAP1	HSC-LX2，CCl₄诱导的小鼠肝纤维化模型
miR-129-5p^［43］	NF-κB	PEG3	CCl₄诱导的大鼠肝纤维化模型
lncRNA
lncRNA-HEIM^［44］	TGF-β/SMAD	SMAD4	HSC-LX2
lncRNA-MBI-52^［45］	SMAD4	miR-466g	HSC-LX2，CCl₄诱导的小鼠肝纤维化模型
lncRNA-LFAR1^［46］	TGF-β1/SMAD2/3和Notch	SMAD2/3和Notch	人HEK293T，小鼠AML-12，原代HSC和肝细胞
			CCl₄诱导和胆管结扎（BDL）诱导的小鼠肝纤维化模型
lncRNA-ANXA2P2（小鼠Anxa6）^［47］	TGF-β1/PI3K/Akt	miR-9-5p	CCl₄诱导的小鼠肝纤维化模型
lncRNA-Met与lncRNA-Nox4^［48］	PI3K/Akt	PI3K	CCl₄诱导的小鼠肝纤维化模型
lncRNA-MIAT^［49］	YAP/EMT	miR-3085-5p	肝硬化患者，小鼠原代HSC，CCl₄诱导的小鼠肝纤维化模型
lncRNA-HSER^［50］	Hippo-YAP和Notch	C5AR1	小鼠AML-12，小鼠原代肝细胞、HSC、LSEC和KC，人L02和HEK293T
			肝血管瘤患者，CCl₄诱导的小鼠肝纤维化模型
circRNA
circUbe2k^［51］	TGF-β2	miR-149-5p	HSC-LX2，CCl₄诱导的小鼠肝纤维化模型
circDIDO1^［52］	PTEN/AKT	miR-141-3p	HSC-LX2，肝衰竭患者
川芎嗪^［53］	TGF-β/SMAD	miR-145	HSC-T6，乙醇诱导的胆道闭锁大鼠肝纤维化模型
达沙替尼^［54］	TGF-β/SMAD7	miR-17-5p	TAA诱导的小鼠肝纤维化模型
	Wnt5a/β-catenin	miR-378-3p
艾代拉里斯（Idelalisib）^［55］	TGF-β/SMAD	SMAD3	CCl₄诱导的小鼠肝纤维化模型
	PI3K/AKT	miR-124-3p

下载: 导出CSV

参考文献(55)

[1]	WANG FS, FAN JG, ZHANG Z, et al. The global burden of liver disease: The major impact of China[J]. Hepatology, 2014, 60( 6): 2099- 2108. DOI: 10.1002/hep.27406.
[2]	OMATA M, CHENG AL, KOKUDO N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: A 2017 update[J]. Hepatol Int, 2017, 11( 4): 317- 370. DOI: 10.1007/s12072-017-9799-9.
[3]	KISSELEVA T, BRENNER D. Molecular and cellular mechanisms of liver fibrosis and its regression[J]. Nat Rev Gastroenterol Hepatol, 2021, 18( 3): 151- 166. DOI: 10.1038/s41575-020-00372-7.
[4]	DEWIDAR B, MEYER C, DOOLEY S, et al. TGF-β in hepatic stellate cell activation and liver fibrogenesis-updated 2019[J]. Cells, 2019, 8( 11): 1419. DOI: 10.3390/cells8111419.
[5]	CHEN L, YANG T, LU DW, et al. Central role of dysregulation of TGF-β/SMAD in CKD progression and potential targets of its treatment[J]. Biomed Pharmacother, 2018, 101: 670- 681. DOI: 10.1016/j.biopha.2018.02.090.
[6]	WALTON KL, JOHNSON KE, HARRISON CA. Targeting TGF-β mediated SMAD signaling for the prevention of fibrosis[J]. Front Pharmacol, 2017, 8: 461. DOI: 10.3389/fphar.2017.00461.
[7]	TARIQ S, KOLOKO BL, MALIK A, et al. Tectona grandis leaf extract ameliorates hepatic fibrosis: Modulation of TGF-β/SMAD signaling pathway and upregulating MMP3/TIMP1 ratio[J]. J Ethnopharmacol, 2021, 272: 113938. DOI: 10.1016/j.jep.2021.113938.
[8]	ELRAZIK NAA, EL-MESERY M, EL-SHISHTAWY MM. Sesamol protects against liver fibrosis induced in rats by modulating lysophosphatidic acid receptor expression and TGF-β/SMAD3 signaling pathway[J]. Naunyn Schmiedebergs Arch Pharmacol, 2022, 395( 8): 1003- 1016. DOI: 10.1007/s00210-022-02259-7.
[9]	SUN YM, LIU BY, XIE JP, et al. Aspirin attenuates liver fibrosis by suppressing TGF‑β1/smad signaling[J]. Mol Med Rep, 2022, 25( 5): 181. DOI: 10.3892/mmr.2022.12697.
[10]	SHU GW, DAI CX, YUSUF A, et al. Limonin relieves TGF-β-induced hepatocyte EMT and hepatic stellate cell activation in vitro and CCl₄-induced liver fibrosis in mice via upregulating SMAD7 and subsequent suppression of TGF-β/SMAD cascade[J]. J Nutr Biochem, 2022, 107: 109039. DOI: 10.1016/j.jnutbio.2022.109039.
[11]	ZHANG YE. Non-smad signaling pathways of the TGF-β family[J]. Cold Spring Harb Perspect Biol, 2017, 9( 2): a022129. DOI: 10.1101/cshperspect.a022129.
[12]	VARGAS-POZADA EE, RAMOS-TOVAR E, ACERO-HERNÁNDEZ C, et al. Caffeine mitigates experimental nonalcoholic steatohepatitis and the progression of thioacetamide-induced liver fibrosis by blocking the MAPK and TGF-β/SMAD3 signaling pathways[J]. Ann Hepatol, 2022, 27( 2): 100671. DOI: 10.1016/j.aohep.2022.100671.
[13]	ABDEL-RAHMAN RF, FAYED HM, ASAAD GF, et al. The involvement of TGF-β1/FAK/α-SMA pathway in the antifibrotic impact of rice bran oil on thioacetamide-induced liver fibrosis in rats[J]. PLoS One, 2021, 16( 12): e0260130. DOI: 10.1371/journal.pone.0260130.
[14]	WANG HL, CHE JY, CUI K, et al. Schisantherin A ameliorates liver fibrosis through TGF-β1mediated activation of TAK1/MAPK and NF-κB pathways in vitro and in vivo[J]. Phytomedicine, 2021, 88: 153609. DOI: 10.1016/j.phymed.2021.153609.
[15]	YAN YF, ZENG JF, XING LH, et al. Extra- and intra-cellular mechanisms of hepatic stellate cell activation[J]. Biomedicines, 2021, 9( 8): 1014. DOI: 10.3390/biomedicines9081014.
[16]	EL-FADALY AA, AFIFI NA, EL-ERAKY W, et al. Fisetin alleviates thioacetamide-induced hepatic fibrosis in rats by inhibiting Wnt/β-catenin signaling pathway[J]. Immunopharmacol Immunotoxicol, 2022, 44( 3): 355- 366. DOI: 10.1080/08923973.2022.2047198.
[17]	LEE IH, IM E, LEE HJ, et al. Apoptotic and antihepatofibrotic effect of honokiol via activation of GSK3β and suppression of Wnt/β-catenin pathway in hepatic stellate cells[J]. Phytother Res, 2021, 35( 1): 452- 462. DOI: 10.1002/ptr.6824.
[18]	PORTA C, PAGLINO C, MOSCA A. Targeting PI3K/akt/mTOR signaling in cancer[J]. Front Oncol, 2014, 4: 64. DOI: 10.3389/fonc.2014.00064.
[19]	FEDELE CG, OOMS LM, HO M, et al. Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers[J]. Proc Natl Acad Sci USA, 2010, 107( 51): 22231- 22236. DOI: 10.1073/pnas.1015245107.
[20]	XIU AY, DING Q, LI Z, et al. Doxazosin attenuates liver fibrosis by inhibiting autophagy in hepatic stellate cells via activation of the PI3K/Akt/mTOR signaling pathway[J]. Drug Des Devel Ther, 2021, 15: 3643- 3659. DOI: 10.2147/DDDT.S317701.
[21]	LEE SW, KIM SM, HUR W, et al. Tenofovir disoproxil fumarate directly ameliorates liver fibrosis by inducing hepatic stellate cell apoptosis via downregulation of PI3K/Akt/mTOR signaling pathway[J]. PLoS One, 2021, 16( 12): e0261067. DOI: 10.1371/journal.pone.0261067.
[22]	LIN X, WEI YY, LI Y, et al. Tormentic acid ameliorates hepatic fibrosis in vivo by inhibiting glycerophospholipids metabolism and PI3K/Akt/mTOR and NF-κB pathways: Based on transcriptomics and metabolomics[J]. Front Pharmacol, 2022, 13: 801982. DOI: 10.3389/fphar.2022.801982.
[23]	LUEDDE T, SCHWABE RF. NF-κB in the liver: Linking injury, fibrosis and hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2011, 8( 2): 108- 118. DOI: 10.1038/nrgastro.2010.213.
[24]	TANIGUCHI K, KARIN M. NF-κB, inflammation, immunity and cancer: Coming of age[J]. Nat Rev Immunol, 2018, 18( 5): 309- 324. DOI: 10.1038/nri.2017.142.
[25]	ZHAO YC, LIU XL, DING CB, et al. Dihydromyricetin reverses thioacetamide-induced liver fibrosis through inhibiting NF-κB-mediated inflammation and TGF-β1-regulated of PI3K/Akt signaling pathway[J]. Front Pharmacol, 2021, 12: 783886. DOI: 10.3389/fphar.2021.783886.
[26]	de SOUZA BASSO B, HAUTE GV, ORTEGA-RIBERA M, et al. Methoxyeugenol deactivates hepatic stellate cells and attenuates liver fibrosis and inflammation through a PPAR-ɣ and NF-kB mechanism[J]. J Ethnopharmacol, 2021, 280: 114433. DOI: 10.1016/j.jep.2021.114433.
[27]	RAJ D, SHARMA V, UPADHYAYA A, et al. Swertia purpurascens Wall ethanolic extract mitigates hepatic fibrosis and restores hepatic hepcidin levels via inhibition of TGFβ/SMAD/NFκB signaling in rats[J]. J Ethnopharmacol, 2022, 284: 114741. DOI: 10.1016/j.jep.2021.114741.
[28]	SHARAWY MH, EL-KASHEF DH, SHAABAN AA, et al. Anti-fibrotic activity of sitagliptin against concanavalin A-induced hepatic fibrosis. Role of Nrf2 activation/NF-κB inhibition[J]. Int Immunopharmacol, 2021, 100: 108088. DOI: 10.1016/j.intimp.2021.108088.
[29]	NOGUCHI S, SAITO A, NAGASE T. YAP/TAZ signaling as a molecular link between fibrosis and cancer[J]. Int J Mol Sci, 2018, 19( 11): 3674. DOI: 10.3390/ijms19113674.
[30]	LI CX, ZHANG RR, ZHAN YT, et al. Resveratrol inhibits hepatic stellate cell activation via the hippo pathway[J]. Mediators Inflamm, 2021, 2021: 3399357. DOI: 10.1155/2021/3399357.
[31]	MA TT, CHENG HL, LI TX, et al. N-Acetyl-l-tryptophan inhibits CCl₄-induced hepatic fibrogenesis via regulating TGF-β1/SMAD and Hippo/YAP1 signal[J]. Bioorg Chem, 2022, 126: 105899. DOI: 10.1016/j.bioorg.2022.105899.
[32]	KIM EK, CHOI EJ. Compromised MAPK signaling in human diseases: An update[J]. Arch Toxicol, 2015, 89( 6): 867- 882. DOI: 10.1007/s00204-015-1472-2.
[33]	CAI SY, WU LJ, YUAN SY, et al. Carvacrol alleviates liver fibrosis by inhibiting TRPM7 and modulating the MAPK signaling pathway[J]. Eur J Pharmacol, 2021, 898: 173982. DOI: 10.1016/j.ejphar.2021.173982.
[34]	KATAOKA S, UMEMURA A, OKUDA K, et al. Honokiol acts as a potent anti-fibrotic agent in the liver through inhibition of TGF-β1/SMAD signaling and autophagy in hepatic stellate cells[J]. Int J Mol Sci, 2021, 22( 24): 13354. DOI: 10.3390/ijms222413354.
[35]	ZHANG TP, HU JJ, WANG XM, et al. microRNA-378 promotes hepatic inflammation and fibrosis via modulation of the NF-κB-TNFα pathway[J]. J Hepatol, 2019, 70( 1): 87- 96. DOI: 10.1016/j.jhep.2018.08.026.
[36]	HE C, SHU B, ZHOU YX, et al. The miR-139-5p/peripheral myelin protein 22 axis modulates TGF-β-induced hepatic stellate cell activation and CCl₄-induced hepatic fibrosis in mice[J]. Life Sci, 2021, 276: 119294. DOI: 10.1016/j.lfs.2021.119294.
[37]	YANG X, SHU B, ZHOU YX, et al. Ppic modulates CCl₄-induced liver fibrosis and TGF-β-caused mouse hepatic stellate cell activation and regulated by miR-137-3p[J]. Toxicol Lett, 2021, 350: 52- 61. DOI: 10.1016/j.toxlet.2021.06.021.
[38]	ZHOU QY, YANG HM, LIU JX, et al. microRNA-497 induced by Clonorchis sinensis enhances the TGF-β/SMAD signaling pathway to promote hepatic fibrosis by targeting SMAD7[J]. Parasit Vectors, 2021, 14( 1): 472. DOI: 10.1186/s13071-021-04972-3.
[39]	GAO HB, WANG XM, MA HX, et al. LncRNA CCAT2, involving miR-34a/TGF-β1/SMAD4 signaling, regulate hepatic stellate cells proliferation[J]. Sci Rep, 2022, 12( 1): 21199. DOI: 10.1038/s41598-022-25738-6.
[40]	WANG N, LI XJ, ZHONG ZY, et al. 3D hESC exosomes enriched with miR-6766-3p ameliorates liver fibrosis by attenuating activated stellate cells through targeting the TGFβRII-SMADS pathway[J]. J Nanobiotechnology, 2021, 19( 1): 437. DOI: 10.1186/s12951-021-01138-2.
[41]	WANG H, WANG Z, WANG YR, et al. miRNA-130b-5p promotes hepatic stellate cell activation and the development of liver fibrosis by suppressing SIRT4 expression[J]. J Cell Mol Med, 2021, 25( 15): 7381- 7394. DOI: 10.1111/jcmm.16766.
[42]	YANG JF, XU CQ, WU MM, et al. microRNA-124 inhibits hepatic stellate cells inflammatory cytokines secretion by targeting IQGAP1 through NF-κB pathway[J]. Int Immunopharmacol, 2021, 95: 107520. DOI: 10.1016/j.intimp.2021.107520.
[43]	ZHU YZ, HU YB, CHENG XY, et al. Elevated miR-129-5p attenuates hepatic fibrosis through the NF-κB signaling pathway via PEG3 in a carbon CCl₄ rat model[J]. J Mol Histol, 2021, 52( 3): 491- 501. DOI: 10.1007/s10735-020-09949-7.
[44]	YAO J, LIN CH, JIANG JJ, et al. lncRNA-HEIM facilitated liver fibrosis by up-regulating TGF-β expression in long-term outcome of chronic hepatitis B[J]. Front Immunol, 2021, 12: 666370. DOI: 10.3389/fimmu.2021.666370.
[45]	LI YZ, LIU PX, WEI FP. Long non‑coding RNA MBI‑52 inhibits the development of liver fibrosis by regulating the microRNA‑466g/SMAD4 signaling pathway[J]. Mol Med Rep, 2022, 25( 1): 33. DOI: 10.3892/mmr.2021.12549.
[46]	ZHANG K, HAN XH, ZHANG Z, et al. The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFβ and Notch pathways[J]. Nat Commun, 2017, 8( 1): 144. DOI: 10.1038/s41467-017-00204-4.
[47]	LIAO JM, ZHANG Z, YUAN Q, et al. The mouse Anxa6/miR-9-5p/Anxa2 axis modulates TGF-β1-induced mouse hepatic stellate cell(mHSC) activation and CCl₄-caused liver fibrosis[J]. Toxicol Lett, 2022, 362: 38- 49. DOI: 10.1016/j.toxlet.2022.04.004.
[48]	WANG Y, XIAO X, WANG XB, et al. Identification of differentially expressed long noncoding RNAs and pathways in liver tissues from rats with hepatic fibrosis[J]. PLoS One, 2021, 16( 10): e0258194. DOI: 10.1371/journal.pone.0258194.
[49]	ZHAN YT, TAO QQ, MENG QS, et al. LncRNA-MIAT activates hepatic stellate cells via regulating Hippo pathway and epithelial-to-mesenchymal transition[J]. Commun Biol, 2023, 6( 1): 285. DOI: 10.1038/s42003-023-04670-z.
[50]	ZHANG K, ZHANG MX, YAO QB, et al. The hepatocyte-specifically expressed lnc-HSER alleviates hepatic fibrosis by inhibiting hepatocyte apoptosis and epithelial-mesenchymal transition[J]. Theranostics, 2019, 9( 25): 7566- 7582. DOI: 10.7150/thno.36942.
[51]	ZHU S, CHEN X, WANG JN, et al. Circular RNA circUbe2k promotes hepatic fibrosis via sponging miR-149-5p/TGF-β2 axis[J]. FASEB J, 2021, 35( 6): e21622. DOI: 10.1096/fj.202002738R.
[52]	MA L, WEI JF, ZENG YL, et al. Mesenchymal stem cell-originated exosomal circDIDO1 suppresses hepatic stellate cell activation by miR-141-3p/PTEN/AKT pathway in human liver fibrosis[J]. Drug Deliv, 2022, 29( 1): 440- 453. DOI: 10.1080/10717544.2022.2030428.
[53]	QIU JL, ZHANG GF, CHAI YN, et al. Ligustrazine attenuates liver fibrosis by targeting miR-145 mediated transforming growth factor-β/smad signaling in an animal model of biliary atresia[J]. J Pharmacol Exp Ther, 2022, 381( 3): 257- 265. DOI: 10.1124/jpet.121.001020.
[54]	ZAAFAN MA, ABDELHAMID AM. Dasatinib ameliorates thioacetamide-induced liver fibrosis: Modulation of miR-378 and miR-17 and their linked Wnt/β-catenin and TGF-β/smads pathways[J]. J Enzyme Inhib Med Chem, 2022, 37( 1): 118- 124. DOI: 10.1080/14756366.2021.1995379.
[55]	LI XH, LI HL, ZHANG SS, et al. Protective effect of Idelalisib on carbon tetrachloride-induced liver fibrosis via microRNA-124-3P/phosphatidylinositol-3-hydroxykinase signalling pathway[J]. J Cell Mol Med, 2021, 25( 24): 11185- 11197. DOI: 10.1111/jcmm.17039.