外泌体影响肝星状细胞和肝巨噬细胞促进肝纤维化/肝硬化的发病机制研究

摘要/Abstract

摘要： 作为细胞间通讯的关键载体,外泌体在肝星状细胞(hepatic stellate cells, HSCs)和肝巨噬细胞之间传递复杂的信号分子,从而深刻影响肝纤维化和肝硬化的发病机制。多种细胞来源的外泌体携带促纤维化的微小RNA、长非编码RNA和蛋白质,这些外泌体被HSCs摄取后,能够激活其内部的关键信号通路,从而促进HSCs的活化、增殖、迁移和细胞外基质的过度分泌。同时,外泌体也介导HSCs对巨噬细胞的反向调节,加剧炎症和纤维化。此外,RNA的N6-甲基腺苷修饰也参与其中,促进纤维化。然而,外泌体的作用并非全为促进性,间充质干细胞(mesenchymal stem cells,MSC)等细胞来源的外泌体携带抗纤维化分子(如miR-30a-5p),能够抑制HSC活化或促进巨噬细胞向抗炎表型转化,为肝硬化和肝纤维化的治疗提供了新的思路。本综述旨在探讨外泌体影响HSCs和肝巨噬细胞促进肝纤维化/肝硬化的发病机制。

关键词: 肝纤维化, 肝硬化, 外泌体, 肝星状细胞, 肝巨噬细胞

郭芮嫣, 吴旭, 樊郑阳, 王晓忠. 外泌体影响肝星状细胞和肝巨噬细胞促进肝纤维化/肝硬化的发病机制研究[J]. 肝脏, 2026, 31(3): 312-316.

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参考文献

[1] Wang S, Gao S, Ye W, et al.The emerging importance role of m6A modification in liver disease[J].Biomed Pharmacother,2023,162:114669.
[2] Ghazwani M, Zhang Y, Gao X, et al.Anti-fibrotic effect of thymoquinone on hepatic stellate cells[J].Phytomedicine, 2014, 21(3):254-260.
[3] Hu X, Ge Q, Zhang Y, et al.A review of the effect of exosomes from different cells on liver fibrosis[J].Biomed Pharmacother, 2023, 161:114415.
[4] Zhang Y, Ren L, Tian Y, et al.Signaling pathways that activate hepatic stellate cells during liver fibrosis[J].Front Med (Lausanne), 2024, 11:1454980.
[5] Cheng D, Chai J, Wang H,et al.Hepatic macrophages: key players in the development and progression of liver fibrosis[J].Liver Int, 2021, 41(10):2279-2294.
[6] Wang Z, Du K, Jin N,et al.Macrophage in liver fibrosis: identities and mechanisms[J].Int Immunopharmacol, 2023, 120:110357.
[7] Liu Y, Zheng Y, Yang Y,et al.Exosomes in liver fibrosis: the role of modulating hepatic stellate cells and immune cells, and prospects for clinical applications[J].Front Immunol, 2023, 14:1133297.
[8] Garbuzenko D V.Pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis[J].World J Clin Cases, 2022, 10(12):3662-3676.
[9] Tang M, Guo C, Sun M, et al.Effective delivery of osteopontin small interference RNA using exosomes suppresses liver fibrosis via TGF-β1 signaling[J].Front Pharmacol.2022, 13:882243.
[10] Wang L, Wang Y, Quan J.Exosomes derived from natural killer cells inhibit hepatic stellate cell activation and liver fibrosis[J].Hum Cell, 2020, 33(3):582-589.
[11] Hu M, Wang Y, Liu Z, et al.Hepatic macrophages act as a central hub for relaxin-mediated alleviation of liver fibrosis[J].Nat Nanotechnol, 2021, 16(4):466-477.
[12] Gao C C,Bai J, Han H, et al.The versatility of macrophage heterogeneity in liver fibrosis[J].Front Immunol.2022, 13:968879.
[13] Kim D M,Pan Q, Liu Z, et al.GHSR-Foxo1 signaling in macrophages promotes liver fibrosis via inflammatory response and hepatic stellate cell activation[J].Adv Sci (Weinh).2025, 12(33):e04223.
[14] Peng Y, Li Z, Chen S, et al.DHFR silence alleviated the development of liver fibrosis by affecting the crosstalk between hepatic stellate cells and macrophages[J].J Cell Mol Med.2021, 25(21):10049-10060.
[15] Luo X, Chen K, Zhang J,et al.Ghrelin alleviates liver fibrosis by triggering HSCs ferroptosis via regulating injured hepatocyte-derived exosomal lncMALAT1/GPX4 pathway[J].FASEB J, 2025, 39(2):e70297.
[16] Sun J, Shi L, Xiao T, et al.microRNA-21, via the HIF-1α/VEGF signaling pathway, is involved in arsenite-induced hepatic fibrosis through aberrant cross-talk of hepatocytes and hepatic stellate cells[J].Chemosphere, 2021, 266:129177.
[17] Li W, Chen L, Zhou Q, et al.Liver macrophage-derived exosomal miRNA-342-3p promotes liver fibrosis by inhibiting HPCAL1 in stellate cells[J].Hum Genomics, 2025, 19(1):9.
[18] Cai X, Wang J, Wang J, et al.Intercellular crosstalk of hepatic stellate cells in liver fibrosis: new insights into therapy[J].Pharmacol Res, 2020, 155:104720.
[19] Hu Z, Chen G, Yan C, et al.Autophagy affects hepatic fibrosis progression by regulating macrophage polarization and exosome secretion[J].Environ Toxicol, 2023, 38(7):1665-1677.
[20] Luan S H,Yang Y Q,Ye M P,et al.ASIC1a promotes hepatic stellate cell activation through the exosomal miR-301a-3p/BTG1 pathway[J].Int J Biol Macromol. 2022, 211:128-139.
[21] Ma J, Li Y, Chen M, et al.hMSCs-derived exosome circCDK13 inhibits liver fibrosis by regulating the expression of MFGE8 through miR-17-5p/KAT2B[J].Cell Biol Toxicol, 2023, 39(2):1-22.
[22] Azizsoltani A, Hatami B, Zali M R,et al.Obeticholic acid-loaded exosomes attenuate liver fibrosis through dual targeting of the FXR signaling pathway and ECM remodeling[J].Biomed Pharmacother.2023, 168:115777.
[23] Ezhilarasan D.Hepatic stellate cells in the injured liver: perspectives beyond hepatic fibrosis[J].J Cell Physiol,2022, 237(1):436-449.
[24] Shu B,Zhou Y X,Li H, et al.The METTL3/MALAT1/PTBP1/USP8/TAK1 axis promotes pyroptosis and M1 polarization of macrophages and contributes to liver fibrosis[J].Cell Death Discov, 2021, 7(1):368.
[25] Gao Y, Li L, Zhang S N,et al.HepG2.2.15-derived exosomes facilitate the activation and fibrosis of hepatic stellate cells[J].World J Gastroenterol.2024,30(19):2553-2563.
[26] Chong S, Chen G, Dang Z,et al.Echinococcus multilocularis drives the polarization of macrophages by regulating the RhoA-MAPK signaling pathway and thus affects liver fibrosis[J].Bioengineered.2022, 13(4):8747-8758.
[27] Zhang Y, Zhang S, Liao P, et al.3D hESC exosome-derived circular RNA hsa_circ_0076798 inhibits M1 macrophage inflammatory response and alleviates liver fibrosis by suppressing TNF/NF-κB pathway through miR-1184/DICER1 Axis[J].Biotechnol Bioeng.2025, 122(11):3073-3089.
[28] Yan Y, Zeng J, Xing L, et al.Extra-and intra-cellular mechanisms of hepatic stellate cell activation[J].Biomedicines, 2021, 9(8):1014.
[29] Zhang T, Jing J, Liang Y, et al.Resveratrol-stimulated macrophage exosomes delivering lncRNA Snhg6 inhibit liver fibrosis by modulating the NF-κB pathway[J].Genomics, 2025, 117(3):111043.
[30] Zhou Y, Ren H, Dai B,et al.Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts[J].J Exp Clin Cancer Res, 2018, 37(1):324.
[31] Ismail M, Fadul M M, Taha R, et al.Dynamic role of exosomal long non-coding RNA in liver diseases: pathogenesis and diagnostic aspects[J].Hepatol Int, 2024, 18(6):1715-1730.
[32] Ye H, Luo H, He Q,et al.Personalized human umbilical cord mesenchymal stem cell-derived exosome pre-treatment based on the simulation of scar microenvironment characteristics: a promising approach for early scar treatment[J].Mol Biol Rep, 2025, 52(1):747.
[33] Diwan R, Gaytan S L, Bhatt H N,et al.Liver fibrosis pathologies and potentials of RNA based therapeutics modalities[J].Drug Deliv Transl Res, 2024,14(10):2743-2770.