信号素在肝脏疾病中的作用及其机制

穆巴热斯·曼吾拉; 丁轩; 罗壹丹; 梁清帅; 周旭; 刘玉武

doi:10.12449/JCH260632

信号素在肝脏疾病中的作用及其机制

DOI: 10.12449/JCH260632

穆巴热斯·曼吾拉^{1, 2},
丁轩^{1, 2},
罗壹丹^{1, 2},
梁清帅^{1, 2},
周旭^{1, 3},
刘玉武^{1, 4, , ,}

1.
新疆医科大学基础医学院病理学教研室，乌鲁木齐 830017
2.
新疆医科大学第一临床医学院，乌鲁木齐 830054
3.
新疆医科大学第六临床医学院，乌鲁木齐 830054
4.
新疆地方病分子生物学重点实验室，乌鲁木齐 830017

基金项目:

新疆医科大学大学生创新计划项目 (S202410760081)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：穆巴热斯·曼吾拉负责撰写论文及绘制图片；丁轩、罗壹丹负责设计论文框架及修改论文；梁清帅、周旭负责文献检索及整理；刘玉武负责指导、审阅文章及最后定稿。

详细信息

通信作者:
刘玉武， xjlyw-007@126.com （ORCID： 0000-0002-6329-120X）

计量
- 文章访问数: 7
- HTML全文浏览量: 1
- PDF下载量: 2
- 被引次数: 0
出版历程
- 收稿日期: 2025-09-26
- 录用日期: 2025-11-05
- 出版日期: 2026-06-25

Role and mechanism of semaphorins in liver diseases

Manwula MUBARESI^{1, 2},
Xuan DING^{1, 2},
Yidan LUO^{1, 2},
Qingshuai LIANG^{1, 2},
Xu ZHOU^{1, 3},
Yuwu LIU^{1, 4
, ,
,}

1.
Department of Pathology，School of Basic Medical Sciences，Xinjiang Medical University，Urumqi 830017，China
2.
The First Clinical Medical College of Xinjiang Medical University，Urumqi 830054，China
3.
The Sixth Clinical Medical College of Xinjiang Medical University，Urumqi 830054，China
4.
Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases，Urumqi 830017，China

Research funding:

Xinjiang Medical University Undergraduate Innovation Training Program Project (S202410760081)

More Information

Corresponding author: LIU Yuwu， xjlyw-007@126.com （ORCID： 0000-0002-6329-120X）

摘要

摘要: 肝脏是维持人体生命活动的重要代谢器官，其功能紊乱与多种肝脏疾病密切相关。近年来，越来越多的研究表明，信号素（SEMA）可通过与其受体神经丛蛋白和神经毡蛋白的相互作用，在肝脏疾病免疫炎症反应、肿瘤进展及纤维化等病理过程中发挥重要作用。本文系统综述了不同SEMA在病毒性肝炎、肝癌、肝纤维化、非酒精性脂肪性肝病及肝脏缺血再灌注损伤中的表达、功能及分子机制，并探讨了SEMA在肝脏疾病诊断与治疗中的潜在应用价值，旨在为肝脏疾病的精准诊断与靶向治疗提供新思路。
- 信号素类 /
- 肝疾病 /
- 神经丛蛋白 /
- 神经毡蛋白
Abstract: The liver is a vital metabolic organ sustaining human life activities， and its dysfunction is closely associated with various liver diseases. In recent years， an increasing number of studies have shown that semaphorins （SEMA） play a significant role in pathological processes such as immune inflammatory response， tumor progression， and fibrosis in liver diseases by interacting with their receptors plexins and neuropilins. This article reviews the expression， functions， and molecular mechanisms of different SEMA in viral hepatitis， hepatocellular carcinoma， liver fibrosis， nonalcoholic fatty liver disease， and hepatic ischemia-reperfusion injury， and it also explores the potential application value of SEMA in the diagnosis and treatment of liver diseases， in order to provide new ideas for precise diagnosis and targeted treatment of liver diseases.
- Semaphorins /
- Liver Disease /
- Plexin /
- Neuropilin

HTML全文

注： HSC，肝星状细胞；CAF，肿瘤相关成纤维细胞；HCC，肝细胞癌；SEMA，信号素；Nrp-1，神经毡蛋白1；ITGB1，整合素β1；NF-κB，核因子κB；IL-6，白细胞介素6；TGF-β1，转化生长因子β1；TGF-βR，转化生长因子β受体；AP1，激活蛋白1；Akt，蛋白激酶B；Gli，神经胶质瘤相关癌基因同源物；c-Myc，细胞源性髓细胞增生癌基因蛋白；plexin，神经丛蛋白；miRNA，微RNA；SEMA6A-AS1，SEMA6A反义RNA 1。

图 1 信号素在肝细胞癌中的作用机制

Figure 1. Mechanism of semaphorins in hepatocellular carcinoma

下载: 全尺寸图片幻灯片

注： PDGF，血小板衍生生长因子；PDGFR，血小板衍生生长因子受体；Nrp，神经毡蛋白；c-Abl，非受体酪氨酸激酶Abelson；Rac1，Ras相关的C3肉毒杆菌毒素底物1；SEMA，信号素；TGF-β，转化生长因子β；ITGB1，整合素B1；Akt，蛋白激酶B；ERK，胞外信号调节激酶；Plexin，神经丛蛋白；CD72，白细胞分化抗原72；IL-13，白细胞介素13；STAT6，信号转导与转录激活因子6。

图 2 信号素在肝纤维化中的作用机制

Figure 2. Mechanism of semaphorins in hepatic fibrosis

下载: 全尺寸图片幻灯片

表 1 信号素在肝疾病中的生物学作用及其具体机制

Table 1. Biological functions and specific mechanisms of semaphorins in liver diseases

生物学作用	信号素	受体	具体机制	参考文献
促进炎症反应	SEMA6B	plexin-A2	促巨噬细胞释放细胞因子并激活多种促炎通路	［9］
促进炎症反应	SEMA7A	plexin-C1	激活中性粒细胞和巨噬细胞，加剧肝脏缺血再灌注损伤	［46-47］
促进细胞凋亡	SEMA6B	—	诱导肝细胞周期G0/G1期停滞	［9］
免疫调节	SEMA4D	—	反映乙型肝炎的进展程度	［11-12］
抑制HCC恶性生物学行为	SEMA5A	—	促进肝癌细胞凋亡	［22-23］
促进HCC恶性生物学行为	SEMA3C	Nrp-1、ITGB1	激活Akt/Gli1/c-Myc通路，维持肿瘤干细胞特性；重塑基质微环境；诱导索拉非尼耐药	［14］
	SEMA4C	—	受多种miRNA调控，促进肝细胞癌增殖、迁移、侵袭和上皮-间质转化	［3， 13， 17-18］
	SEMA6A	—	导致肌动蛋白应力纤维丢失和肌动蛋白细胞骨架重塑	［28］
促进肿瘤细胞肝转移	Ⅳ类SEMA	plexin-B2	激活转录因子KLF4并抑制上皮-间质转化，促进转移灶形成	［19］
促进肿瘤细胞肝转移	SEMA5A	plexin-B3	增强瓦博格效应，促进胰腺导管腺癌细胞增殖和肝转移	［24］
促进肝纤维化	SEMA3C	Nrp-1、Nrp-2	促PDGF受体自磷酸化，通过c-Abl激活Rac1促进 SMAD2磷酸化，增强TGF-β信号通路	［34-35］
促进肝纤维化	SEMA7A	ITGB1	激活Akt和ERK通路，调控TGF-β信号通路	［37］
	SEMA4D	plexin-B1、CD72	促进TGF-β1/SMAD和IL-13/STAT6信号通路	［38］
影响脂质代谢	SEMA3A	Nrp-1	激活LIM激酶1并磷酸化丝切蛋白，减少肝窦内皮细胞的窗孔	［42］
影响脂质代谢	SEMA7A	plexin-B1	R148W突变增强蛋白激酶C-α的激活，促进脂肪酸和甘油三酯的合成与摄取	［44］
注：SEMA，信号素；plexin，神经丛蛋白；Nrp，神经毡蛋白；ITGB1，整合素B1；Akt，蛋白激酶B；Gli1，胶质瘤相关癌基因同源物1；c-Myc，细胞源性髓细胞增生癌基因蛋白；miRNA，微RNA；PDGF，血小板衍生生长因子；c-Abl，非受体酪氨酸激酶Abelson；Rac1，Ras相关的C3肉毒杆菌毒素底物1；TGF-β，转化生长因子β；ERK，胞外信号调节激酶；CD72，白细胞分化抗原72；IL-13，白细胞介素13；STAT6，信号转导与转录激活因子6。

下载: 导出CSV

参考文献(47)

[1]	XU BN, ZHANG X, XIE WF. Role of hepatocyte nuclear factor 4α in liver diseases and its regulatory mechanism[J]. Chin J Dig, 2023, 43( 7): 491- 494. DOI: 10.3760/cma.j.cn311367-20230217-00073. 徐搏男, 张新, 谢渭芬. 肝细胞核因子4α在肝脏疾病中的作用及调控机制[J]. 中华消化杂志, 2023, 43( 7): 491- 494. DOI: 10.3760/cma.j.cn311367-20230217-00073.
[2]	DEVARBHAVI H, ASRANI SK, ARAB JP, et al. Global burden of liver disease: 2023 update[J]. J Hepatol, 2023, 79( 2): 516- 537. DOI: 10.1016/j.jhep.2023.03.017.
[3]	MA SY, PU C. miR-129-2-3p binds SEMA4C to regulate HCC development and inhibit the EMT[J]. Mutat Res, 2024, 829: 111872. DOI: 10.1016/j.mrfmmm.2024.111872.
[4]	GONG L, PAN GQ. Advances in axon guidance molecule SEMA5A[J]. Chongqing Med, 2020, 49( 15): 2566- 2571. DOI: 10.3969/j.issn.1671-8348.2020.15.034. 龚琳, 潘国庆. 神经导向分子SEMA5A的研究进展[J]. 重庆医学, 2020, 49( 15): 2566- 2571. DOI: 10.3969/j.issn.1671-8348.2020.15.034.
[5]	JIANG YX, LIU XY, GUO ZH, et al. Research progress on relationship between semaphorins family and asthma[J]. Int J Immunol, 2022, 45( 6): 651- 655. DOI: 10.3760/cma.j.issn.1673-4394.2022.06.016. 蒋云秀, 刘欣怡, 郭子涵, 等. 信号素家族与哮喘的研究进展[J]. 国际免疫学杂志, 2022, 45( 6): 651- 655. DOI: 10.3760/cma.j.issn.1673-4394.2022.06.016.
[6]	LU YJ, ZHANG SL, XU Q, et al. Advances in effect of Semaphorin family and their receptors on tumor angiogenesis[J]. Acad J Chin PLA Med Sch, 2015, 36( 10): 1056- 1060. DOI: 10.3969/j.issn.2095-5227.2015.10.025. 鲁艳杰, 张淑玲, 许倩, 等. Semaphorin家族及其受体对肿瘤血管生成影响的研究进展[J]. 解放军医学院学报, 2015, 36( 10): 1056- 1060. DOI: 10.3969/j.issn.2095-5227.2015.10.025.
[7]	WAGNER W, OCHMAN B, WAGNER W. Semaphorin 6 family-an important yet overlooked group of signaling proteins involved in cancerogenesis[J]. Cancers, 2023, 15( 23): 5536. DOI: 10.3390/cancers15235536.
[8]	LI J, LIANG X, JIANG J, et al. PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF[J]. Gut, 2022, 71( 1): 163- 175. DOI: 10.1136/gutjnl-2020-323395.
[9]	YANG H, CAI Q, XIN JJ, et al. SEMA6B induces macrophage-mediated inflammation and hepatocyte apoptosis in hepatitis B virus-related acute-on-chronic liver failure[J]. Theranostics, 2024, 14( 13): 5200- 5218. DOI: 10.7150/thno.97007.
[10]	PAPIC N, ZIDOVEC LEPEJ S, GORENEC L, et al. The association of semaphorins 3C, 5A and 6D with liver fibrosis stage in chronic hepatitis C[J]. PLoS One, 2018, 13( 12): e0209481. DOI: 10.1371/journal.pone.0209481.
[11]	WEN X, HE YJ, YUAN QQ, et al. Expression of Sema4D in peripheral blood T cells and serum of patients with hepatitis B cirrhosis and its clinical significance[J]. J Clin Hepatol, 2023, 39( 4): 810- 817. DOI: 10.3969/j.issn.1001-5256.2023.04.011. 温雪, 何昱静, 袁倩倩, 等. Sema4D在乙型肝炎肝硬化患者外周血T淋巴细胞和血清中的表达及意义[J]. 临床肝胆病杂志, 2023, 39( 4): 810- 817. DOI: 10.3969/j.issn.1001-5256.2023.04.011.
[12]	YANG SQ, WANG L, PAN W, et al. MMP2/MMP9-mediated CD100 shedding is crucial for inducing intrahepatic anti-HBV CD8 T cell responses and HBV clearance[J]. J Hepatol, 2019, 71( 4): 685- 698. DOI: 10.1016/j.jhep.2019.05.013.
[13]	MA SY, ZHANG BC, LI XR, et al. miR-3612 regulates the malignant biological behaviors of hepatocellular carcinoma cells via targeting SEMA4C[J]. Chin J Cancer Biother, 2024, 31( 3): 231- 239. DOI: 10.3872/j.issn.1007-385x.2024.03.004. 马思源, 张博超, 李贤锐, 等. miR-3612靶向SEMA4C调控肝细胞癌细胞的恶性生物学行为[J]. 中国肿瘤生物治疗杂志, 2024, 31( 3): 231- 239. DOI: 10.3872/j.issn.1007-385x.2024.03.004.
[14]	PENG H, YANG M, FENG K, et al. Semaphorin 3C(Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression[J]. Signal Transduct Target Ther, 2024, 9( 1): 169. DOI: 10.1038/s41392-024-01887-0.
[15]	LIU HJ, YE H, LI XZ. Effect of microrna-138 on epithelial-Mesenchymal transition and invasion of breast cancer cells by targeting semaphorin 4C[J]. Bioengineered, 2021, 12( 2): 10117- 10125. DOI: 10.1080/21655979.2021.2000733.
[16]	HUANG YD, BAI QY, YU HB, et al. Circ-POLA2-mediated miR-138-5p/SEMA4C axis affects colon cancer cell activities[J]. Acta Biochim Pol, 2023, 70( 3): 517- 523. DOI: 10.18388/abp.2020_6457.
[17]	LU J, LIN YX, LI FY, et al. miR-205 suppresses tumor growth, invasion, and epithelial-mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma[J]. FASEB J, 2018. DOI: 10.1096/fj.201800113R.[ Epub ahead of print]
[18]	YU ZJ, DU YH, LI HY, et al. miR-642 serves as a tumor suppressor in hepatocellular carcinoma by regulating SEMA4C and p38 MAPK signaling pathway[J]. Oncol Lett, 2020, 20( 4): 74. DOI: 10.3892/ol.2020.11935.
[19]	BORRELLI C, ROBERTS M, ELETTO D, et al. In vivo interaction screening reveals liver-derived constraints to metastasis[J]. Nature, 2024, 632( 8024): 411- 418. DOI: 10.1038/s41586-024-07715-3.
[20]	NAGY GN, ZHAO XF, KARLSSON R, et al. Structure and function of Semaphorin-5A glycosaminoglycan interactions[J]. Nat Commun, 2024, 15( 1): 2723. DOI: 10.1038/s41467-024-46725-7.
[21]	ZUO QZ, YANG YK, LYU YJ, et al. Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis[J]. Cell Rep, 2023, 42( 3): 112164. DOI: 10.1016/j.celrep.2023.112164.
[22]	WANG Y, ZHANG S, ZHANG JG, et al. Effect of SEMA5A on cell proliferation and apoptosis of hepatocellular carcinoma and possible mechanism[J]. Chin J Cancer Prev Treat, 2023, 30( 7): 397- 405. DOI: 10.16073/j.cnki.cjcpt.2023.07.04. 王燕, 张曙, 章建国, 等. SEMA5A对肝细胞癌增殖及凋亡的影响及可能机制[J]. 中华肿瘤防治杂志, 2023, 30( 7): 397- 405. DOI: 10.16073/j.cnki.cjcpt.2023.07.04.
[23]	JIANG CX, ZHANG XX, ZHANG S, et al. Expression and clinical significance of SEMA5A and Ki-67 in hepatocellular carcinoma[J]. Chin J Clin Exp Pathol, 2023, 39( 2): 151- 156. DOI: 10.13315/j.cnki.cjcep.2023.02.005. 姜晨霞, 章小霞, 张曙, 等. 肝细胞癌中Semaphorin5A及Ki-67的表达及其临床意义[J]. 临床与实验病理学杂志, 2023, 39( 2): 151- 156. DOI: 10.13315/j.cnki.cjcep.2023.02.005.
[24]	WANG K, HE M, FAN X, et al. SEMA5A-PLXNB3 axis promotes PDAC liver metastasis outgrowth through enhancing the Warburg effect[J]. J Immunol Res, 2023, 2023: 3274467. DOI: 10.1155/2023/3274467.
[25]	MA Y, ZHANG ZY, CAO XL, et al. Semaphorin 6A phase separation sustains a histone lactylation-dependent lactate buildup in pathological angiogenesis[J]. Proc Natl Acad Sci USA, 2025, 122( 16): e2423677122. DOI: 10.1073/pnas.2423677122.
[26]	JI J, XU YX, XIE MR, et al. VHL-HIF-2α axis-induced SEMA6A upregulation stabilized β-catenin to drive clear cell renal cell carcinoma progression[J]. Cell Death Dis, 2023, 14( 2): 83. DOI: 10.1038/s41419-023-05588-4.
[27]	SONG ZB, YU Y, ZHANG GP, et al. Genomic instability of mutation-derived gene prognostic signatures for hepatocellular carcinoma[J]. Front Cell Dev Biol, 2021, 9: 728574. DOI: 10.3389/fcell.2021.728574.
[28]	YU SM, ZHANG M, LI SL, et al. Long noncoding RNA semaphorin 6A-antisense RNA 1 reduces hepatocellular carcinoma by promoting semaphorin 6A mRNA degradation[J]. World J Gastroenterol, 2025, 31( 13): 102527. DOI: 10.3748/wjg.v31.i13.102527.
[29]	LORIA R, LAQUINTANA V, SCALERA S, et al. SEMA6A/RhoA/YAP axis mediates tumor-stroma interactions and prevents response to dual BRAF/MEK inhibition in BRAF-mutant melanoma[J]. J Exp Clin Cancer Res, 2022, 41( 1): 148. DOI: 10.1186/s13046-022-02354-w.
[30]	LORIA R, BON G, PEROTTI V, et al. Sema6A and Mical1 control cell growth and survival of BRAFV600E human melanoma cells[J]. Oncotarget, 2015, 6( 5): 2779- 2793. DOI: 10.18632/oncotarget.2995.
[31]	SEGARRA M, OHNUKI H, MARIC D, et al. Semaphorin 6A regulates angiogenesis by modulating VEGF signaling[J]. Blood, 2012, 120( 19): 4104- 4115. DOI: 10.1182/blood-2012-02-410076.
[32]	LIAO ZH, XIE ZY. Research progress in molecular mechanism of hepatic fibrosis and related therapeutic targets[J]. J Jilin Univ Med Ed, 2024, 50( 5): 1450- 1456. DOI: 10.13481/j.1671-587X.20240532. 廖昭辉, 谢正元. 肝纤维化发病的分子机制及其相关治疗靶点的研究进展[J]. 吉林大学学报(医学版), 2024, 50( 5): 1450- 1456. DOI: 10.13481/j.1671-587X.20240532.
[33]	ABIDAN BHTYE, GUO JS. Metabolic adaptation of activated hepatic stellate cells during hepatic fibrogenesis[J]. Chin J Cell Biol, 2021, 43( 10): 2054- 2060. DOI: 10.11844/cjcb.2021.10.0014. 阿比丹·拜合提亚尔, 郭津生. 肝纤维化发生时活化肝星状细胞的代谢改变[J]. 中国细胞生物学学报, 2021, 43( 10): 2054- 2060. DOI: 10.11844/cjcb.2021.10.0014.
[34]	de ANGELIS RIGOTTI F, WIEDMANN L, HUBERT MO, et al. Semaphorin 3C exacerbates liver fibrosis[J]. Hepatology, 2023, 78( 4): 1092- 1105. DOI: 10.1097/HEP.0000000000000407.
[35]	CAO S, YAQOOB U, DAS A, et al. Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-beta signaling in hepatic stellate cells[J]. J Clin Invest, 2010, 120( 7): 2379- 2394. DOI: 10.1172/JCI41203.
[36]	CAO XY, TANG YH, YUAN M. Research progress of semaphorin 7A in immune inflammation and nervous system diseases[J]. Curr Immunol, 2022, 42( 4): 340- 343. 曹湘玉, 汤永红, 袁梅. 信号素7A在免疫炎症及神经系统疾病中的研究进展[J]. 现代免疫学, 2022, 42( 4): 340- 343.
[37]	de MINICIS S, RYCHLICKI C, AGOSTINELLI L, et al. Semaphorin 7A contributes to TGF-β-mediated liver fibrogenesis[J]. Am J Pathol, 2013, 183( 3): 820- 830. DOI: 10.1016/j.ajpath.2013.05.030.
[38]	WANG LF, LIAO Y, YANG RB, et al. Sja-miR-71a in Schistosome egg-derived extracellular vesicles suppresses liver fibrosis caused by schistosomiasis via targeting semaphorin 4D[J]. J Extracell Vesicles, 2020, 9( 1): 1785738. DOI: 10.1080/20013078.2020.1785738.
[39]	ŠAMADAN L, PAPIĆ N, MIJIĆ M, et al. Do semaphorins play a role in development of fibrosis in patients with nonalcoholic fatty liver disease?[J]. Biomedicines, 2022, 10( 12): 3014. DOI: 10.3390/biomedicines10123014.
[40]	PLEIN A, FANTIN A, RUHRBERG C. Neuropilin regulation of angiogenesis, arteriogenesis, and vascular permeability[J]. Microcirculation, 2014, 21( 4): 315- 323. DOI: 10.1111/micc.12124.
[41]	ZHANG F, ZARKADA G, HAN J, et al. Lacteal junction zippering protects against diet-induced obesity[J]. Science, 2018, 361( 6402): 599- 603. DOI: 10.1126/science.aap9331.
[42]	EBERHARD D, BALKENHOL S, KÖSTER A, et al. Semaphorin-3A regulates liver sinusoidal endothelial cell porosity and promotes hepatic steatosis[J]. Nat Cardiovasc Res, 2024, 3( 6): 734- 753. DOI: 10.1038/s44161-024-00487-z.
[43]	PAN Q, LUO G, QU JQ, et al. A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis[J]. EMBO Mol Med, 2021, 13( 11): e14563. DOI: 10.15252/emmm.202114563.
[44]	ZHAO N, ZHANG XX, DING JJ, et al. SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface[J]. JCI Insight, 2022, 7( 15): e154113. DOI: 10.1172/jci.insight.154113.
[45]	LI SJ, XU TF, YUAN GD, et al. Advances in basic and clinical research on hepatic ischemia-reperfusion injury[J]. Chin J Exp Surg, 2023, 40( 10): 1925- 1930. DOI: 10.3760/cma.j.cn421213-20230207-01048. 李双江, 徐挺锋, 袁观斗, 等. 肝脏缺血再灌注损伤的临床与基础研究进展[J]. 中华实验外科杂志, 2023, 40( 10): 1925- 1930. DOI: 10.3760/cma.j.cn421213-20230207-01048.
[46]	WORZFELD T, OFFERMANNS S. Semaphorins and plexins as therapeutic targets[J]. Nat Rev Drug Discov, 2014, 13( 8): 603- 621. DOI: 10.1038/nrd4337.
[47]	KÖNIG K, GRANJA T, ECKLE VS, et al. Inhibition of plexin C1 protects against hepatic ischemia-reperfusion injury[J]. Crit Care Med, 2016, 44( 8): e625-32. DOI: 10.1097/CCM.0000000000001609.