Advances in understanding of role of CXCL12 and its receptors CXCR4/CXCR7 in liver-related diseases

doi:10.3877/cma.j.issn.1674-0785.2025.09.011

Abstract

Abstract:

In acute or chronic liver injury and malignant liver tumors, the expression of CXC chemokine ligand 12 (CXCL12) is significantly increased. CXCL12 can activate two different chemokine receptors-CXC chemokine receptor-4 (CXCR4) and CXC chemokine receptor-7 (CXCR7)-to play different roles. The CXCL12-CXCR7 axis modulates acute liver injury and liver regeneration, while CXCL12-CXCR4 signaling promotes the progression of liver fibrosis by activating hepatic stellate cells and recruiting bone marrow mesenchymal stem cells from the bone marrow. In addition, CXCL12 and its receptors can promote tumor growth, invasion, metastasis, and angiogenesis. This article summarizes the recent progress in the understanding of CXCL12 and its receptors CXCR4/CXCR7 in liver-related diseases, with the aim of providing new directions and ideas for the diagnosis and treatment of liver-related diseases.

Key words: Liver regeneration, CXC chemokine ligand 12, CXC chemokine receptor-4/7, Liver fibrosis, Hepatocellular carcinoma

Longfu Xi, Jiangtao Li. Advances in understanding of role of CXCL12 and its receptors CXCR4/CXCR7 in liver-related diseases[J]. Chinese Journal of Clinicians(Electronic Edition), 2025, 19(09): 714-719.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhlcyszz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-0785.2025.09.011

https://zhlcyszz.cma-cmc.com.cn/EN/Y2025/V19/I09/714

References 45

1	Wilson GC, Freeman CM, Kuethe JW, et al. CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice [J]. Am J Physiol Gastrointest Liver Physiol, 2015, 308: G702-G709.
2	Pawig L, Klasen C, Weber C, et al. Diversity and inter-connections in the CXCR4 chemokine receptor/ligand family:molecular perspectives [J]. Front Immunol, 2015, 6: 429.
3	Lu C, Zhang Y, Sun C, et al. Stromal cell derived factor-1 promotes hepatic insulin resistance via inhibiting hepatocyte lipophagy [J]. J Cell Mol Med, 2025; 29(2): e70352.
4	Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1 [J]. Nature, 1996, 382: 635-638.
5	Yoshie O, Imai T, Nomiyama H. Chemokines in immunity [J]. AdvImmunol, 2001, 78: 57-110.
6	Loetscher M, Geiser T, O'Reilly T, et al. Cloning of a human seven transmembrane domain receptor, LESTR, that is highly expressed in leukocytes [J]. J Biol Chem, 1994, 269: 232-237.
7	Bleul CC, Farzan M, Choe H, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry [J]. Nature, 1996, 382: 829-833.
8	Oberlin E, Amara A, Bachelerie F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1 [J]. Nature, 1996, 382: 833-835.
9	Ma Q, Jones D, Borghesani PR, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4-and SDF-1-deficient mice [J]. Proc Natl Acad Sci USA, 1998, 95: 9448-9453.
10	Tachibana K, Hirota S, Iizasa H, et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract [J]. Nature, 1998, 393: 591-594.
11	Libert F, Parmentier M, Lefort A, et al. Selective amplification and cloning of four new members of the G protein-coupled receptor family [J]. Science, 1989, 244(4904): 569-72.
12	Shimizu N, Soda Y, Kanbe K, et al. A putative G protein-coupled receptor, RDC1, is a novel coreceptor for human and simian immunodeficiency viruses [J]. J Virol, 2000, 74: 619-626.
13	Ding BS, Cao Z, Lis R, et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis [J]. Nature, 2014, 505: 97-102.
14	DeLeve LD, Wang X, Wang L. VEGF-sdf1 recruitment of CXCR7⁺bone marrow progenitors of liver sinusoidal endothelial cells promotes rat liver regeneration [J]. Am J Physiol Gastrointest Liver Physiol, 2016, 310: G739-G746.
15	Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning [J]. Am J Physiol Gastrointest Liver Physiol, 2003, 284: G15-G26.
16	Ito C, Haraguchi R, Ogawa K, et al. Demethylation in promoter region of severely damaged hepatocytes enhances chemokine receptor CXCR4 gene expression [J]. Histochem Cell Biol, 2023, 160(5): 407-418.
17	Otaka F, Ito Y, Nakamoto S, et al. Macrophages contribute to liver repair after monocrotaline-induced liver injury via SDF-1/CXCR4 [J]. Experimental and therapeutic medicine, 2021, 22(1): 668.
18	Zheng J, Li H, He L, et al. Preconditioning of umbilical cord-derived mesenchymal stem cells by rapamycin increases cell migration and ameliorates liver ischaemia/reperfusion injury in mice via the CXCR4/CXCL12 axis [J]. Cell Prolif, 2019, 52(2): e12546.
19	Krzystek-Korpacka M, Fleszar MG, Fortuna P, et al. Modulation of prostanoids profile and counter-regulation of SDF-1α/CXCR4 and VIP/VPAC2 expression by sitagliptin in non-diabetic rat model of hepatic ischemia-reperfusion injury [J]. Int J Mol Sci, 2021, 22(23): 13155.
20	Abe Y, Uchinami H, Kudoh K, et al. Liver epithelial cells proliferate under hypoxia and protect the liver from ischemic injury via expression of HIF-1 alpha target genes [J]. Surgery, 2012, 152(5): 869-878.
21	Wilson GC, Freeman CM, Kuethe JW, et al. CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice [J]. Am J Physiol Gastrointest Liver Physiol, 2015, 308(8): G702-G709.
22	Ding F, Liu Y, Li J, et al. TC14012 enhances the anti-fibrosis effects of UC-MSCs on the liver by reducing collagen accumulation and ameliorating inflammation [J]. Stem Cell Res Ther, 2024, 15(1): 44.
23	Chen N, Sun Y, Luo P, et al. Association of CXCR4 gene expression and promoter methylation with chronic hepatitis B-related fibrosis/cirrhosis [J]. Int Immunopharmacology, 2024, 139: 112686.
24	Feng Y, Broder CC, Kennedy PE, et al. HIV-1 entry cofactor:functional cDNA cloning of a seven-transmembrane,G protein-coupled receptor [J]. Science, 1996, 272: 872-877.
25	Hong F, Saiman Y, Si C, et al. X4 Human immunodeficiency virus type 1 gp120 promotes human hepatic stellate cell activation and collagen I expression through interactions with CXCR4 [J]. PLoS One, 2012, 7: e33659.
26	Saiman Y, Agarwal R, Hickman DA, et al. CXCL12 induces hepatic stellate cell contraction through a calcium-independent pathway [J]. Am J Physiol Gastrointest Liver Physiol, 2013, 305: G375-G382.
27	Saiman Y, Jiao J, Fiel MI, et al. Inhibition of the CXCL12/CXCR4 chemokine axis with AMD3100,a CXCR4 small molecule inhibitor,worsens murine hepatic injury [J]. Hepatol Res, 2015, 45: 794-803.
28	Chow LN, Schreiner P, Ng BY, et al. Impact of a CXCL12/CXCR4 antagonist inbleomycin (BLM) induced pulmonary fibrosis and carbon tetrachloride (CCl4) induced hepatic fibrosis in mice [J]. PLoS One, 2016, 11: e0151765.
29	Tsuchiya A, Imai M, Kamimura H, et al. Increased susceptibility to severe chronic liver damage in CXCR4 conditional knock-out mice [J]. Dig Dis Sci, 2012, 57: 2892-2900.
30	Liu Y, Yang X, Jing YY, et al. Contribution and Mobilization of Mesenchymal Stem Cells in a mouse model of carbon tetrachloride-induced liver fibrosis [J]. Sci Rep, 2015, 5: 17762.
31	Cui H, Yang W. Single-cell RNA sequencing analysis reveals potential key prognostic markers in hepatocellular carcinoma [J]. Discov Oncol, 2024, 15(1): 747.
32	Pan XF, Kaminga AC, Wen SW, et al. Chemokines in hepatocellular carcinoma:a meta-analysis [J]. Carcinogenesis, 2020, 41(12): 1682-1694.
33	Chen RX, Song HY, Dong YY, et al. Dynamic expression patterns of differential proteins during early invasion of hepatocellular carcinoma [J]. PLoS One, 2014, 9: e88543.
34	Zhao H, Guo LY, Zhao H, et al. CXCR4 over-expression and survival in cancer: a system review and meta-analysis [J]. Oncotarget, 2015, 6(7): 5022-5040.
35	Wang X, Zhang W, Ding Y, et al. CRISPR/Cas9-mediated genome engineering of CXCR4 decreases the malignancy of hepatocellular carcinoma cells in vitro and in vivo [J]. Oncol Rep, 2017, 37(6): 3565-3571.
36	Kun-Ming C, Chih-Hsien C, Chen-Fang L, et al. Potential anticancer effect of celastrol on hepatocellular carcinoma by suppressing CXCR4-related signal and impeding tumor growth in vivo [J]. Arch Med Res, 2020, 51(4): 297-302.
37	Wu WJ, Wang J, Chen F, et al. Exploration of heterogeneity and recurrence signatures in hepatocellular carcinoma [J]. Mol Ooncol, 2025, 19(8):2388-2411.
38	Lin L, Han MM, Wang F, et al. CXCR7 stimulates MAPK signaling to regulate hepatocellular carcinoma progression [J]. Cell Death Dis, 2014, 5(10): e1488.
39	Liu CH, Chan KM, Chiang T, et al. Dual-functional nanoparticles targeting CXCR4 and delivering antiangiogenic siRNA ameliorate liver fibrosis [J]. Mol Pharm, 2016, 13(7): 2253-2262.
40	Ullah A, Chen G, Zhang Y, et al. A new approach based on CXCR4-targeted combination liposomes for the treatment of liver fibrosis [J]. Biomater Sci, 2022, 10(10): 2650-2664.
41	Morita S, Lei PJ, Shigeta K, et al. Combination CXCR4 and PD-1 blockade enhances intratumoral dendritic cell activation and immune responses against hepatocellular carcinoma [J]. Cancer Immunol Res, 2025, 13(2): 162-170.
42	杨振林, 邹伟伟. 索拉非尼防治大鼠肝癌肝移植术后肿瘤转移复发的研究 [J/OL]. 中华临床医师杂志(电子版), 2011, 5(2): 335-342.
43	Steinberg M, Silva M. Plerixafor: a chemokine receptor-4 antagonist for mobilization of hematopoietic stem cells for transplantation after high-dose chemotherapy for non-Hodgkin's lymphoma or multiple myeloma [J]. Clin Ther, 2010, 32(5): 821-843.
44	Kajiyama H, Shibata K, Terauchi M, et al. Involvement of SDF-1alpha/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma [J]. Int J Cancer, 2008, 122(1): 91-99.
45	Song JS, Chang CC, Wu CH, et al. A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment [J]. Proc Natl Acad Sci USA, 2021, 118(13): e2015433118.

[1]	Xiuling Yang, Wenhui Wang, Jie Yang, Qiang Lu. Contrast-enhanced ultrasound features of dual-phenotype versus classical hepatocellular carcinoma and risk factors for dual-phenotype hepatocellular carcinoma [J]. Chinese Journal of Medical Ultrasound (Electronic Edition), 2025, 22(08): 761-767.
[2]	Yijun Gu, Yiran Li, Yi Qian, Dong Jiang. Prediction of microvascular invasion and postoperative recurrence in hepatocellular carcinoma based on quantitative indices derived from contrast-enhanced ultrasonography [J]. Chinese Journal of Medical Ultrasound (Electronic Edition), 2025, 22(05): 451-461.
[3]	Shenyu Zhang, Jizhou Wang. Surgical strategies for multifocal hepatocellular carcinoma - from the perspective of surgeons [J]. Chinese Journal of Laparoscopic Surgery(Electronic Edition), 2025, 18(05): 264-270.
[4]	Jian Cao, Zhanao Meng, Ke Zhang, Yue Zhang, Yahao Guo, Sisi Deng, Tao Luo, Xuan Zhu, Jie Qin, Chao Li, Tianhao Tang, Yingkun Chen, Qing Xiang. Development and validation of a bimodal model for liver fibrosis staging based on serological indicators and MRI [J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2025, 14(06): 902-911.
[5]	Jianwen Li, Ying Chen, Xi Chen, Xiaodan Zong. Application of Gd-EOB-DTPA enhanced MRI in differential diagnosis of small well-differentiated hepatocellular carcinoma and dysplastic nodules [J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2025, 14(06): 875-881.
[6]	Shuirong Lin, Zimin Song, Xi Yu, Shaoqiang Li, Yunpeng Hua, Shunli Shen. Effect of preoperative antiviral therapy on post-hepatectomy liver failure for HBV-associated hepatocellular carcinoma [J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2025, 14(05): 700-706.
[7]	Hui Yuan, Luzhong Zhou, Henian Tang, Juhua Pan. Evaluation of the prognostic of LMR and PHR in patients with hepatocellular carcinoma undergoing radiofrequency ablation [J]. Chinese Journal of Digestion and Medical Imageology(Electronic Edition), 2025, 15(06): 635-641.
[8]	Hanyu Meng, Ruixue Cao, Yangyang Zhang, Xuan Xin, Liquan Bi, Xiaohong Liu. Expression and clinicopathological analysis of MYCT1 and FAS in HBV infection-associated hepatocellular carcinoma [J]. Chinese Journal of Digestion and Medical Imageology(Electronic Edition), 2025, 15(04): 311-316.
[9]	Yuanqing He, Leiming Guo, Pei Feng, Chunning Ma, Xin Yue. Correlation study between multimodal parameters of gadoxetic acid disodium enhanced MRI and disease severity in patients with primary hepatocellular carcinoma [J]. Chinese Journal of Digestion and Medical Imageology(Electronic Edition), 2025, 15(04): 317-325.
[10]	Yamin Li, Xinlei Lyu, Xiumei Shi, Yueyun Wang, Ou Sheng, Gaofeng Bu, Song Cheng, Shining Xie. Influence factors of liver fibrosis reversal in patients with chronic hepatitis B treated with tenofovir alafenamide fumarate and receiving virological response [J]. Chinese Journal of Digestion and Medical Imageology(Electronic Edition), 2025, 15(04): 359-363.
[11]	Ying Ran, Ruiyun Liu, Xinyu Wang, Jiaqi Gu, Zongze Han, Jiwen Li, Hui Yang, Xiaoran Wang, Bangmao Wang, Lu Zhou. Transient elastography in autoimmune hepatitis: performance and determinants for liver fibrosis diagnosis [J]. Chinese Journal of Clinicians(Electronic Edition), 2025, 19(09): 651-658.
[12]	Shilun Wu, Changyu Yao, Li Xu, Zhishan Di, Qi Xia, Wenbing Sun, Jian Kong. Progress in understanding the role of tumor-associated macrophages in hepatocellular carcinoma angiogenesis [J]. Chinese Journal of Clinicians(Electronic Edition), 2025, 19(05): 388-391.
[13]	Haixiao Zhang, Weixin Ren, Junpeng Gu. Hepatic Arterial Infusion Chemotherapy Combined with Portal Vein Endovascular Brachytherapy Stent in the Treatment of Primary Hepatocellular Carcinoma with Type Ⅲ Portal Vein Tumor Thrombus [J]. Chinese Journal of Interventional Radiology(Electronic Edition), 2025, 13(04): 314-321.
[14]	Suyi Ye, Ruohan Zhang, Yi Deng, Xiaoming Chen, Jing Zhang, Jing Li, Rongde Xu, Wei Cui. Clinical efficacy and safety analysis of M-TACE in the treatment of unresectable large hepatocellular carcinoma [J]. Chinese Journal of Interventional Radiology(Electronic Edition), 2025, 13(04): 330-337.
[15]	Qiangqiang Xia, Xing Li, Lizhou Wang. Artificial Intelligence in Hepatocellular Carcinoma Diagnosis and Treatment Decisions [J]. Chinese Journal of Interventional Radiology(Electronic Edition), 2025, 13(04): 373-377.

Please choose a citation manager

Content to export