Journal of Shandong University (Health Sciences) ›› 2025, Vol. 63 ›› Issue (4): 59-68.doi: 10.6040/j.issn.1671-7554.0.2024.1106

• Preclinical Medicine • Previous Articles    

Furin regulates mitophagy and liver fibrosis progression through phosphatase and tensin homolog-long in mouse

SONG Yanwei1, FU Zhenmei2, XU Jingyi1, MA Mingze1, SUN Linlin3   

  1. 1. Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China;
    2. Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China;
    3. Department of Interventional Therapy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
  • Published:2025-04-08

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Abstract: Objective To investigate the regulatory role of Furin in the progression of liver fibrosis and the molecular mechanisms involved. Methods Forty C57 mice were randomly divided into the Furin overexpression group and the control group, with 20 mice in each group. The mice were intraperitoneally injected with CCL4 to induce animal models of liver fibrosis for 8 weeks. Four weeks after CCL4 induction, mice in the Furin overexpression group received tail vein injections of Furin expression transfection plasmids until the end of the experiment, while the control group was injected with empty control plasmids. The effect of Furin on the progression of liver fibrosis was investigated. Primary hepatic stellate cells from C57 mice were isolated by the Nycodenz density gradient separation method and cultured in vitro. The expression and localisation of Furin in liver fibrosis/cirrhosis tissues were detected by immunohistochemistry / immunofluorescence staining assay. Protein expression levels in tissues and cells were detected by Western blotting. The proliferation activity of Furin-treated hepatic stellate cells was detected by CCK-8 assay. Changes in cell migration ability of each group by different treatments were detected by Transwell assay. Changes in mitochondrial membrane potential of cells in different treatment groups were detected by flow cytometry and immunofluorescence staining. Results Furin was significantly upregulated in cirrhosis tissues and activated primary hepatic stellate cells. The activation, proliferation and migration abilities of hepatic stellate cells in the Furin treatment group were significantly inhibited(P<0.05), while those in the control group were not affected. The mitochondrial membrane potential of hepatic stellate cells in the Furin treatment group was significantly decreased, while that in the control group was not significantly changed(P<0.05). The mitochondrial membrane potential of stellate cells also decreased significantly in PTEN-L knockdown experiments(P<0.05), while there were no significant changes in the control group. In CCl4-induced liver fibrosis mice, the severity of liver fibrosis was milder in Furin overexpression group mice, while the control group mice showed more severe histological changes of liver fibrosis. Conclusion Furin targets PTEN-L to enhance hepatic stellate cell mitophagy and inhibit hepatic stellate cell activation and progression of liver fibrosis in mice.

Key words: Hepatic stellate cells, Liver fibrosis, Furin, Mitophagy, Phosphatase and tensin homolog-long

CLC Number: 

  • R575
[1] Parola M, Pinzani M. Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues[J]. Mol Aspects Med, 2019, 65: 37-55. doi:10.1016/j.mam.2018.09.002
[2] Park J, Kwon HJ, Sohn W, et al. Risk of liver fibrosis in patients with prediabetes and diabetes mellitus[J]. PLoS One, 2022, 17(6): e0269070.
[3] 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.
[4] 李亚琦, 张荣花, 刘雨潭, 等. miR-194-5p通过Wnt5a抑制肝星状细胞活化[J]. 河北大学学报(自然科学版), 2023, 43(2): 179-187. LI Yaqi, ZHANG Ronghua, LIU Yutan, et al. MiR-194-5p inhibits hepatic stellate cell activation through Wnt5a[J]. Journal of Hebei University(Natural Science Edition), 2023, 43(2): 179-187.
[5] 肖政华, 石以石则, 杨庆万, 等. 基于Wnt/β-catenin信号通路研究扶肝化纤汤抑制HSC-T6活化的作用[J]. 山东大学学报(医学版), 2023, 61(6): 41-46. XIAO Zhenghua, SHI Yishize, YANG Qingwan, et al. Mechanism of fugan huaqian decoction inhibiting HSC-T6 activation via Wnt/β-catenin signaling pathway[J]. Journal of Shandong University(Health Sciences), 2023, 61(6): 41-46.
[6] 贾琳, 孙峰, 董琪琪, 等. YTHDF1调控Fis1对肝星状细胞活化、增殖及迁移能力的影响[J]. 安徽医科大学学报, 2025, 60(1): 49-58. JIA Lin, SUN Feng, DONG Qiqi, et. al, YTHDF1 Regulates the effect of fis1 on the activation, proliferation and migration of hepatic sellate cells[J]. Acta Universitatis Medicinalis Anhui, 2025, 60(1): 49-58.
[7] 劳慧霞, 吴姗姗, 王振常, 等. 柔肝化纤颗粒依赖miR-135a/FOXO1通路调控线粒体自噬抑制大鼠肝纤维化进程[J]. 世界科学技术-中医药现代化, 2024, 26(4): 957-964.
[8] Datta S, Cano M, Satyanarayana G, et al. Mitophagy initiates retrograde mitochondrial-nuclear signaling to guide retinal pigment cell heterogeneity[J]. Autophagy, 2023, 19(3): 966-983.
[9] Dou SD, Zhang JN, Xie XL, et al. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy[J]. Open Med(Wars), 2021, 16(1): 1718-1727.
[10] 曾小晏, 曾子键, 张子欣, 等. 线粒体自噬调节肝纤维化的研究进展[J]. 肝脏, 2024, 29(11): 1315-1318. ZENG Xiaoyan, ZENG Zijian, ZHANG Zixin, et al, Research progress on mitochondrial autophagy regulating liver fibrosis[J]. Chinese Hepatology, 2024, 29(11): 1315-1318.
[11] Eldeeb MA, Esmaili M, Hassan M, et al. The role of PTEN-L in modulating PINK1-parkin-mediated mitophagy[J]. Neurotox Res, 2022, 40(4): 1103-1114.
[12] Nguyen TN, Padman BS, Lazarou M. Deciphering the molecular signals of PINK1/parkin mitophagy[J]. Trends Cell Biol, 2016, 26(10): 733-744.
[13] 许允, 李异. PINK1/Parkin介导的线粒体自噬在异烟肼诱导的肝细胞损伤中的作用[J]. 中南大学学报(医学版), 2022, 47(9): 1200-1207. XU Yun, LI Yi. Regulatory effect of PINK1/Parkin axis on mitophagy in isoniazide-induced hepatocellular injury[J]. Journal of Central South University(Medical Science), 2022, 47(9): 1200-1207.
[14] 于生友. PTEN介导的PINK1/Parkin信号通路在肾小球足细胞线粒体功能障碍中的作用[D]. 广州: 南方医科大学, 2021.
[15] Choi A, Kots ED, Singleton DT, et al. Analysis of the molecular determinants for furin cleavage of the spike protein S1/S2 site in defined strains of the prototype coronavirus murine hepatitis virus(MHV)[J]. Virus Res, 2024, 340: 199283. doi:10.1016/j.virusres.2023.199283
[16] Poyil PK, Siraj AK, Padmaja D, et al. Overexpression of the pro-protein convertase furin predicts prognosis and promotes papillary thyroid carcinoma progression and metastasis through RAF/MEK signaling[J]. Mol Oncol, 2023, 17(7): 1324-1342.
[17] 张欣, 来春林. 前蛋白转化酶在脂质代谢中作用的研究进展[J]. 中西医心脑血管杂志, 2022, 20(6): 1029-1031.
[18] Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424.
[19] Pellicoro A, Ramachandran P, Iredale JP, et al. Liver fibrosis and repair: immune regulation of wound healing in a solid organ[J]. Nat Rev Immunol, 2014, 14: 181-194. doi:10.1038/nri3623
[20] Boursier J, Canivet CM, Costentin C, et al. Impact of type 2 diabetes on the accuracy of noninvasive tests of liver fibrosis with resulting clinical implications[J]. Clin Gastroenterol Hepatol, 2023, 21(5): 1243-1251.
[21] Li Y, Li C, Xiong Y, et al. Didymin ameliorates liver fibrosis by alleviating endoplasmic reticulum stress and glycerophospholipid metabolism: based on transcriptomics and metabolomics[J]. Drug Des Devel Ther, 2022, 16: 1713-1729. doi:10.2147/dDDT.s351092
[22] Mederacke I, Hsu CC, Troeger JS, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology[J]. Nat Commun, 2013, 4: 2823. doi:10.1038/ncomms3823
[23] Coppola I, Brouwers B, Meulemans S, et al. Differential effects of Furin deficiency on insulin receptor processing and glucose control in liver and pancreatic β cells of mice[J]. Int J Mol Sci, 2021, 22(12): 6344.
[24] Solovyeva NI, Gureeva TA, Timoshenko OS, et al. Furin as proprotein convertase and its role in normal and pathological biological processes[J]. Biochem Mosc Suppl Ser B Biomed Chem, 2017, 11(2): 87-100.
[25] Molloy SS, Bresnahan PA, Leppla SH, et al. Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves Anthrax toxin protective antigen[J]. J Biol Chem, 1992, 267(23): 16396-16402.
[26] Hatsuzawa K, Murakami K, Nakayama K. Molecular and enzymatic properties of furin, a Kex2-like endoprotease involved in precursor cleavage at Arg-X-Lys/Arg-Arg sites[J]. J Biochem, 1992, 111(3): 296-301.
[27] Urban D, Lorenz J, Meyborg H, et al. Proprotein convertase furin enhances survival and migration of vascular smooth muscle cells via processing of pro-nerve growth factor[J]. J Biochem, 2013, 153(2): 197-207.
[28] van Kerkhof P, Kralj T, Spanevello F, et al. RSPO3 Furin domain-conjugated liposomes for selective drug delivery to LGR5-high cells[J]. J Control Release, 2023, 356: 72-83. doi:10.1016/j.jconrel.2023.02.025
[29] Li D, Liu X, Zhang L, et al. COVID-19 disease and malignant cancers: the impact for the furin gene expression in susceptibility to SARS-CoV-2[J]. Int J Biol Sci, 2021, 17(14): 3954-3967.
[30] Chen CL, Gupta P, Parashar D, et al. ERBB3-induced furin promotes the progression and metastasis of ovarian cancer via the IGF1R/STAT3 signaling axis[J]. Oncogene, 2020, 39: 2921-2933. doi:10.1038/s41388-020-1194-7
[31] He ZS, Thorrez L, Siegfried G, et al. The proprotein convertase furin is a pro-oncogenic driver in KRAS and BRAF driven colorectal cancer[J]. Oncogene, 2020, 39: 3571-3587. doi:10.1038/s41388-020-1238-z
[32] Yang Y, He MQ, Tian X, et al. Transgenic overexpression of furin increases epileptic susceptibility[J]. Cell Death Dis, 2018, 9: 1058. doi:10.1038/s41419-018-1076-x
[33] Chen Z, Lu S, Xu M, et al. Role of miR-24, furin, and transforming growth factor-β1 signal pathway in fibrosis after cardiac infarction[J]. Med Sci Monit, 2017, 23: 65-70. doi:10.12659/msm.898641
[34] Lee JH, Seo KH, Yang JH, et al. CCCP induces hepatic stellate cell activation and liver fibrogenesis via mitochondrial and lysosomal dysfunction[J]. Free Radic Biol Med, 2024, 225: 181-192. doi:10.1016/j.freeradbiomed.2024.10.259
[35] Ding Q, Xie XL, Wang MM, et al. The role of the apoptosis-related protein BCL-B in the regulation of mitophagy in hepatic stellate cells during the regression of liver fibrosis[J]. Exp Mol Med, 2019, 51: 1-13. doi:10.1038/s12276-018-0199-6
[36] Mary A, Eysert F, Checler F, et al. Mitophagy in Alzheimers disease: molecular defects and therapeutic approaches[J]. Mol Psychiatry, 2023, 28(1): 202-216.
[37] Long M, McWilliams TG. Lipid droplets promote efficient mitophagy[J]. Autophagy, 2023, 19(2): 724-725.
[38] Zhang Y, Fang Q, Wang H, et al. Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage[J]. Autophagy, 2023, 19(1): 75-91.
[39] Shen ZF, Li L, Zhu XM, et al. Current opinions on mitophagy in fungi[J]. Autophagy, 2023, 19(3): 747-757.
[40] Sellars E, Gabra M, Salmena L. The complex landscape of PTEN mRNA regulation[J]. Cold Spring Harb Perspect Med, 2020, 10(6): a036236.
[41] Wang M, Pan Z, Chu X, et al. Chemotherapy-induced PTEN-L secretion promotes the selection of PTEN-deficient tumor cells[J]. J Exp Clin Cancer Res, 2024, 43(1): 140.
[42] Wang L, Wang J, Tang Y, et al. PTEN-L puts a brake on mitophagy[J]. Autophagy, 2018, 14(11): 2023-2025.
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