Liver fibrosis is the common pathological change of chronic liver diseases characterized by increased deposition of extracellular matrix and reduced matrix degradation. In response to liver injury caused by a variety of pathogenic agents, such as virus and alcohol, hepatic stellate cells (HSCs) are differentiated into myofibroblast-like cells and produce excessive collagens, thus resulting in fibrogenesis. Natural killer (NK) cells are the essential innate immune cells in the liver and generally control fibrosis by killing activated HSCs. This review briefly describes the fibrogenesis process and the phenotypic features of hepatic NK cells. Besides, it focuses on the antifibrotic mechanisms of NK cells and explores the potential of activating NK cells as a therapeutic strategy for the disease.
NotasGKisselevaTBrennerD.NK and NKT cells in liver injury and fibrosis.Clin Immunol2009;130:16–26
2.
MehalWImaedaA.Cell death and fibrogenesis.Semin Liver Dis2010; 30:226–31
3.
LianRHKumarV.Murine natural killer cell progenitors and their requirements for development.Semin Immunol2002;14:453–60
4.
ZhengMSunHTianZ.Natural killer cells in liver diseases.Front Med2018;12:269–79
5.
GaoBRadaevaSJeongWI.Activation of natural killer cells inhibits liver fibrosis: a novel strategy to treat liver fibrosis.Expert Rev Gastroenterol Hepatol2007;1:173–80
6.
WangLWangYQuanJ.Exosomes derived from natural killer cells inhibit hepatic stellate cell activation and liver fibrosis.Hum Cell2020;33:582–9
7.
WangLWangYQuanJ.Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy.Mol Med2020;26:81
8.
MussoGCassaderMPaschettaEGambinoR.Bioactive lipid species and metabolic pathways in progression and resolution of nonalcoholic steatohepatitis.Gastroenterology2018;155:282–302
9.
WreeAEguchiAMcGeoughMDPenaCAJohnsonCDCanbayAHoffmanHMFeldsteinAE.NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice.Hepatology2014;59:898–910
10.
GanLTVan RooyenDMKoinaMEMcCuskeyRSTeohNCFarrellGC.Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent.J Hepatol2014;61:1376–84
11.
SekiESchwabeRF.Hepatic inflammation and fibrosis: functional links and key pathways.Hepatology2015;61:1066–79
12.
IwaisakoKJiangCZhangMCongMMoore-MorrisTJParkTJLiuXXuJWangPPaikYHMengFAsagiriMMurrayLAHofmannAFIidaTGlassCKBrennerDAKisselevaT.Origin of myofibroblasts in the fibrotic liver in mice.PANS2014;111:E3297–305
13.
NishioTHuRKoyamaYLiangSRosenthalSBYamamotoGKarinDBaglieriJMaHYXuJLiuXDharDIwaisakoKTauraKBrennerDAKisselevaT.Activated hepatic stellate cells and portal fibroblasts contribute to cholestatic liver fibrosis in MDR2 knockout mice.J Hepatol2019;71:573–85
14.
ZhanSSJiangJXWuJHalstedCFriedmanSLZernMATorokNJ.Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo.Hepatology2006;43:435–43
15.
WatanabeAHashmiAGomesDATownTBadouAFlavellRAMehalWZ.Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9.Hepatology2007;46:1509–18
16.
WanMHanJDingLHuFGaoP.Novel immune subsets and related cytokines: emerging players in the progression of liver fibrosis.Front Med (Lausanne)2021;8:604894
17.
ParolaMPinzaniM.Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues.Mol Aspects Med2019;65:37–55
18.
WreeAMcGeoughMDInzaugaratMEEguchiASchusterSJohnsonCDPenaCAGeislerLJPapouchadoBGHoffmanHMFeldsteinAE.NLRP3 inflammasome driven liver injury and fibrosis: roles of IL-17 and TNF in mice.Hepatology2018;67:736–49
19.
AffoSYuLXSchwabeRF.The role of cancer-associated fibroblasts and fibrosis in liver cancer.Annu Rev Pathol2017;12:153–86
20.
VermijlenDLuoDFroelichCJMedemaJPKummerJAWillemsEBraetFWisseE.Hepatic natural killer cells exclusively kill splenic/blood natural killer-resistant tumor cells by the perforin/granzyme pathway.J Leukoc Biol2002;72:668–76
21.
MikulakJBruniEOrioloFDi VitoCMavilioD.Hepatic natural killer cells: organ-specific sentinels of liver immune homeostasis and physiopathology.Front Immunol2019;10:946
22.
CooperMAFehnigerTATurnerSCChenKSGhaheriBAGhayurTCarsonWECaligiuriMA.Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset.Blood2001;97:3146–51
23.
BrusilovskyMRosentalBShemeshAAppelMYPorgadorA.Human NK cell recognition of target cells in the prism of natural cytotoxicity receptors and their ligands.J Immunotoxicol2012;9:267–74
24.
PegramHJAndrewsDMSmythMJDarcyPKKershawMH.Activating and inhibitory receptors of natural killer cells.Immunol Cell Biol2011;89:216–24
RadaevaSWangLRadaevSJeongWIParkOGaoB.Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1.Am J Physiol Gastrointest Liver Physiol2007;293:G809–16
27.
JinHJiaYYaoZHuangJHaoMYaoSLianNZhangFZhangCChenXBianMShaoJWuLChenAZhengS.Hepatic stellate cell interferes with NK cell regulation of fibrogenesis via curcumin induced senescence of hepatic stellate cell.Cell Signal2017;33:79–85
28.
WangYWangWShenCWangYJiaoMYuWYinHShangXLiangQZhaoC.NKG2D modulates aggravation of liver inflammation by activating NK cells in HBV infection.Sci Rep2017;7:88
29.
StiglundNStrandKCornilletMStalPThorellAZimmerCLNaslundEKarlgrenSNilssonHMellgrenGFernoJHagstromHBjorkstromNK.Retained NK cell phenotype and functionality in non-alcoholic fatty liver disease.Front Immunol2019;10:1255
30.
KahramanASchlattjanMKocabayogluPYildiz-MeziletogluSSchlensakMFingasCDWedemeyerIMarquitanGGieselerRKBabaHAGerkenGCanbayA.Major histocompatibility complex class I-related chains A and B (MIC A/B): a novel role in nonalcoholic steatohepatitis.Hepatology2010;51:92–102
31.
LasoFJMadrugaJIGironJALopezACiudadJSan MiguelJFAlvarez-MonMOrfaoA.Decreased natural killer cytotoxic activity in chronic alcoholism is associated with alcohol liver disease but not active ethanol consumption.Hepatology1997;25:1096–100
32.
GurCDoronSKfir-ErenfeldSHorwitzEAbu-TairLSafadiRMandelboimO.NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis.Gut2012;61:885–93
33.
LiXZhangMLiuJHuangZZhaoQHuangYLiXGaoZ.Intrahepatic NK cells function suppressed in advanced liver fibrosis.Eur J Clin Invest2016;46:864–72
34.
LiWJiangYWangXJinJQiYChiXZhangHFengXNiuJ.Natural killer p46 controls hepatitis B virus replication and modulates liver inflammation.PLoS ONE2015;10:e0135874
35.
NattermannJFeldmannGAhlenstielGLanghansBSauerbruchTSpenglerU.Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C.Gut2006;55:869–77
36.
KramerBKornerCKebschullMGlassnerAEisenhardtMNischalkeHDAlexanderMSauerbruchTSpenglerUNattermannJ.Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis.Hepatology2012;56:1201–13
37.
NelILucarOPetitdemangeCBéziatVLapalusMBédossaPDebréPAsselahTMarcellinPVieillardV.Accumulation of intrahepatic TNF-α-producing NKp44+ NK cells correlates with liver fibrosis and viral load in chronic HCV infection.Medicine (Baltimore)2016;95:e3678
38.
WijayaRSReadSASchibeciSEslamMAzardaryanyMKEl-KhobarKvan der PoortenDLinRYuenLLamVGeorgeJDouglasMWAhlenstielG.KLRG1+ natural killer cells exert a novel antifibrotic function in chronic hepatitis B.J Hepatol2019;71:252–64
39.
Abu-TairLAxelrodJHDoronSOvadyaYKrizhanovskyVGalunEAmerJSafadiR.Natural killer cell-dependent anti-fibrotic pathway in liver injury via toll-like receptor-9.PLoS ONE2013;8:e82571
40.
MuhannaNAbu TairLDoronSAmerJAzzehMMahamidMFriedmanSSafadiR.Amelioration of hepatic fibrosis by NK cell activation.Gut2011;60:90–8
41.
KruegerPDLassenMGQiaoHHahnYS.Regulation of NK cell repertoire and function in the liver.Crit Rev Immunol2011;31:43–52
42.
OgbomoHModyCH.Granule-dependent natural killer cell cytotoxicity to fungal pathogens.Front Immunol2016;7:692
43.
CullenSPMartinSJ.Mechanisms of granule-dependent killing.Cell Death Differ2008;15:251–62
44.
MelhemAMuhannaNBisharaAAlvarezCEIlanYBisharaTHoraniANassarMFriedmanSLSafadiR.Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC.J Hepatol2006;45:60–71
45.
ParkOJeongWIWangLWangHLianZXGershwinMEGaoB.Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride.Hepatology2009;49:1683–94
46.
SagivABiranAYonMSimonJLoweSWKrizhanovskyV.Granule exocytosis mediates immune surveillance of senescent cells.Oncogene2013;32:1971–7
47.
HintermannEBayerMPfeilschifterJMLusterADChristenU.CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation.J Autoimmun2010;35:424–35
48.
FanYZhangWWeiHSunRTianZChenY.Hepatic NK cells attenuate fibrosis progression of non-alcoholic steatohepatitis in dependent of CXCL10-mediated recruitment.Liver Int2020;40:598–608
49.
FugierEMarcheHThéluMAMacek JilkovaZVan CampenhoutNDufeu-DuchesneTLeroyVZarskiJPSturmNMarchePNJouvin-MarcheE.Functions of liver natural killer cells are dependent on the severity of liver inflammation and fibrosis in chronic hepatitis C.PLoS ONE2014;9:e95614
50.
RadaevaSSunRJarugaBNguyenVTTianZGaoB.Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners.Gastroenterology2006;130:435–52
51.
LiTYangYSongHLiHCuiALiuYSuLCrispeINTuZ.Activated NK cells kill hepatic stellate cells via p38/PI3K signaling in a TRAIL-involved degranulation manner.J Leukoc Biol2019;105:695–704
52.
JeongWIParkORadaevaSGaoB.STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity.Hepatology2006;44:1441–51
53.
MaPFGaoCCYiJZhaoJLLiangSQZhaoYYeYCBaiJZhengQJDouKFHanHQinHY.Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice.J Hepatol2017;67:770–9
54.
GlassnerAEisenhardtMKramerBKornerCCoenenMSauerbruchTSpenglerUNattermannJ.NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner.Lab Invest2012;92:967–77
55.
VarchettaSMeleDMantovaniSOlivieroBCremonesiELudovisiSMicheloneGAlessianiMRosatiRMontorsiMMondelliMU.Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection.Hepatology2012;56:841–9
56.
Martínez-ChantarMLDelgadoTCBerazaN.Revisiting the role of natural killer cells in non-alcoholic fatty liver disease.Front Immunol2021;12:640869
ZouYChenTHanMWangHYanWSongGWuZWangXZhuCLuoXNingQ.Increased killing of liver NK cells by Fas/Fas ligand and NKG2D/NKG2D ligand contributes to hepatocyte necrosis in virus-induced liver failure.J Immunol2010;184:466–75
59.
WanZXieGWuYLiuFXinSYouSLiuHLiCLiD.Cytokines elevated in patients with HBV-related acute-on-chronic liver failure promote NK cell mediated cytotoxicity through TRAIL.Dig Liver Dis2016;48:528–35
60.
OhYParkOSwierczewskaMHamiltonJPParkJSKimTHLimSMEomHJoDGLeeCEKechridRMastorakosPZhangCHahnSKJeonOCByunYKimKHanesJLeeKCPomperMGGaoBLeeS.Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells.Hepatology2016;64:209–23
61.
RockeyDCMaherJJJarnaginWRGabbianiGFriedmanSL.Inhibition of rat hepatic lipocyte activation in culture by interferon-gamma.Hepatology1992;16:776–84
62.
HouXYuFManSHuangDZhangYLiuMRenCShenJ.Negative regulation of Schistosoma japonicum egg-induced liver fibrosis by natural killer cells.PLoS Negl Trop Dis2012;6:e1456
63.
WengHLFengDCRadaevaSKongXNWangLLiuYLiQShenHGaoYPMullenbachRMunkerSHuangTChenJLZimmerVLammertFMertensPRCaiWMDooleySGaoB.IFN-gamma inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice.J Hepatol2013;59:738–45
64.
Tosello-TrampontACKruegerPNarayananSLandesSGLeitingerNHahnYS.NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice.Hepatology2016;63:799–812
65.
CuffAOSillitoFDertschnigSHallALuongTVChakravertyRMaleV.The obese liver environment mediates conversion of NK cells to a less cytotoxic ILC1-like phenotype.Front Immunol2019;10:2180
66.
LuoXYTakaharaTKawaiKFujinoMSugiyamaTTsuneyamaKTsukadaKNakaeSZhongLLiXK.IFN-γ deficiency attenuates hepatic inflammation and fibrosis in a steatohepatitis model induced by a methionine- and choline-deficient high-fat diet.Am J Physiol Gastrointest Liver Physiol2013;305:G891–9
67.
HorrasCJLambCLMitchellKA.Regulation of hepatocyte fate by interferon-gamma.Cytokine Growth Factor Rev2011;22:35–43
68.
MoritaMWatanabeYAkaikeT.Protective effect of hepatocyte growth factor on interferon-gamma-induced cytotoxicity in mouse hepatocytes.Hepatology1995;21:1585–93
69.
StegmannKABjörkströmNKVeberHCiesekSRiesePWiegandJHademJSuneethaPVJaroszewiczJWangCSchlaphoffVFytiliPCornbergMMannsMPGeffersRPietschmannTGuzmánCALjunggrenHGWedemeyerH.Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection.Gastroenterology2010;138:1885–97
70.
ChoiWMRyuTLeeJHShimYRKimMHKimHHKimYEYangKKimKChoiSEKimWKimSHEunHSJeongWI.Metabotropic glutamate receptor 5 in natural killer cells attenuates liver fibrosis by exerting cytotoxicity to activated stellate cells.Hepatology2021;74:2170–85
71.
PreisserLMiotCLe Guillou-GuillemetteHBeaumontEFoucherEDGaroEBlanchardSFremauxICroueAFouchardILunel-FabianiFBoursierJRoingeardPCalesPDelnesteYJeanninP.IL-34 and macrophage colony-stimulating factor are overexpressed in hepatitis C virus fibrosis and induce profibrotic macrophages that promote collagen synthesis by hepatic stellate cells.Hepatology2014;60:1879–90
72.
YiHSLeeYSByunJSSeoWJeongJMParkODuesterGHasebaTKimSCParkKGGaoBJeongWI.Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice.Hepatology2014;60:1044–53
73.
YiHSEunHSLeeYSJungJYParkSHParkKGChoiHSSuhJMJeongWI.Treatment with 4-methylpyrazole modulated stellate cells and natural killer cells and ameliorated liver fibrosis in mice.PLoS ONE2015;10:e0127946
74.
JeongWIParkOGaoB.Abrogation of the antifibrotic effects of natural killer cells/interferon-gamma contributes to alcohol acceleration of liver fibrosis.Gastroenterology2008;134:248–58
75.
SzaboGMandrekarPGirouardLCatalanoD.Regulation of human monocyte functions by acute ethanol treatment: decreased tumor necrosis factor-alpha, interleukin-1 beta and elevated interleukin-10, and transforming growth factor-beta production.Alcohol Clin Exp Res1996;20:900–7
76.
WeiXQianJYaoWChenLGuanHChenYXieYLuHZhangZShiLLinX.Hyperactivated peripheral invariant natural killer T cells correlate with the progression of HBV-relative liver cirrhosis.Scand J Immunol2019;90:e12775
77.
JinZSunRWeiHGaoXChenYTianZ.Accelerated liver fibrosis in hepatitis B virus transgenic mice: involvement of natural killer T cells.Hepatology2011;53:219–29
78.
RehermannB.Natural killer cells in viral hepatitis.Cell Mol Gastroenterol Hepatol2015;1:578–88
79.
ChenYWeiHSunRDongZZhangJTianZ.Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells.Hepatology2007;46:706–15
80.
ZhaoJLiYJinLZhangSFanRSunYZhouCShangQLiWZhangZWangFS.Natural killer cells are characterized by the concomitantly increased interferon-gamma and cytotoxicity in acute resolved hepatitis B patients.PLoS ONE2012;7:e49135
81.
AmadeiBUrbaniSCazalyAFisicaroPZerbiniAAhmedPMissaleGFerrariCKhakooSI.Activation of natural killer cells during acute infection with hepatitis C virus.Gastroenterology2010;138:1536–45
82.
YuWHCosgroveCBergerCTCheneyPCKrykbaevaMKimAYLewis-XimenezLLauerGMAlterG.ADCC-mediated CD56(DIM) NK cell responses are associated with early HBsAg clearance in acute HBV infection.Pathog Immun2018;3:2–18
83.
LunemannSSchobelAKahJFittjePHolzemerALangeneckertAEHessLUPochTMartrusGGarcia-BeltranWFKornerCZieglerAERichertLOldhaferKJSchulze Zur WieschJSchrammCDandriMHerkerEAltfeldM.Interactions between KIR3DS1 and HLA-F activate natural killer cells to control HCV replication in cell culture.Gastroenterology2018;155:1366–71
84.
OlivieroBVarchettaSPaudiceEMicheloneGZaramellaMMavilioDDe FilippiFBrunoSMondelliMU.Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections.Gastroenterology2009;137:1151–60
85.
FisicaroPRossiMVecchiAAcerbiGBariliVLaccabueDMontaliIZeccaAPennaAMissaleGFerrariCBoniC.The good and the bad of natural killer cells in virus control: perspective for anti-HBV therapy.Int J Mol Sci2019;20:5080
86.
DunnCBrunettoMReynoldsGChristophidesTKennedyPTLamperticoPDasALopesARBorrowPWilliamsKHumphreysEAffordSAdamsDHBertolettiAMainiMK.Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage.J Exp Med2007;204:667–80
Fernandez-AlvarezSGutierrez-de JuanVZubiete-FrancoIBarbier-TorresLLahozAParesALukaZWagnerCLuSCMatoJMMartinez-ChantarMLBerazaN.TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency.Lab Invest2015;95:223–36
89.
JiangYQinSWeiXLiuXGuanJZhuHChangGChenYLuHQianJWangZShenMLinX.Highly activated TRAIL(+) CD56(bright) NK cells are associated with the liver damage in HBV-LC patients.Immunol Lett2021;232:9–19
90.
OchiMOhdanHMitsutaHOnoeTTokitaDHaraHIshiyamaKZhouWTanakaYAsaharaT.Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice.Hepatology2004;39:1321–31
91.
EisenhardtMGlassnerAKramerBKornerCSibbingBKokordelisPNischalkeHDSauerbruchTSpenglerUNattermannJ.The CXCR3(+)CD56Bright phenotype characterizes a distinct NK cell subset with anti-fibrotic potential that shows dys-regulated activity in hepatitis C.PLoS ONE2012;7:e38846
92.
PoloMLGhiglioneYASalidoJPUriosteAPobleteGSistoAEMartinezARolonMJOjedaDSCahnPETurkGJLauferNL.Liver cirrhosis in HIV/HCV-coinfected individuals is related to NK cell dysfunction and exhaustion, but not to an impaired NK cell modulation by CD4(+) T-cells.J Int AIDS Soc2019;22:e25375
93.
PerpinanEPerez-Del-PulgarSLondonoMCMarinoZBartresCGonzalezPGarcia-LopezMPoseELensSMainiMKFornsXKoutsoudakisG.Cirrhosis hampers early and rapid normalization of natural killer cell phenotype and function in hepatitis C patients undergoing interferon-free therapy.Front Immunol2020;11:129
94.
LiYWangJJGaoSLiuQBaiJZhaoXQHaoYHDingHHZhuFYangDLZhaoXP.Decreased peripheral natural killer cells activity in the immune activated stage of chronic hepatitis B.PLoS ONE2014;9:e86927
95.
HuYWangXWeiYLiuHZhangJShenYCaoJ.Functional inhibition of natural killer cells in a BALB/c mouse model of liver fibrosis induced by schistosoma japonicum infection.Front Cell Infect Microbiol2020;10:598987
96.
ChuangWLLiuHWChangWYChenSCHsiehMYWangLY.Natural killer cell activity in patients with liver cirrhosis relative to severity of liver damage.Dig Dis Sci1991;36:299–302
97.
ShiJZhaoJZhangXChengYHuJLiYZhaoXShangQSunYTuBShiLGaoBWangFSZhangZ.Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-beta-dependent emperipolesis in HBV cirrhotic patients.Sci Rep2017;7:44544
98.
AmerJSalhabANoureddinMDoronSAbu-TairLGhantousRMahamidMSafadiR.Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease.Hepatol Commun2018;2:285–98
99.
PengYHuangKShenLTaoYYLiuCH.Cultured mycelium cordyceps sinensis alleviates CCl4-induced liver inflammation and fibrosis in mice by activating hepatic natural killer cells.Acta Pharmacol Sin2016;37:204–16
100.
PengYYangTHuangKShenLTaoYLiuC.Salvia miltiorrhiza ameliorates liver fibrosis by activating hepatic natural killer cells in vivo and in vitro.Front Pharmacol2018;9:762
101.
XiaYYuBMaCTuYZhaiLYangYLiuDLiuYWuHDanHYouP.Yu Gan long reduces rat liver fibrosis by blocking TGF-beta1/Smad pathway and modulating the immunity.Biomed Pharmacother2018;106:1332–8
102.
van DijkFOlingaPPoelstraKBeljaarsL. Targeted therapies in liver fibrosis: combining the best parts of platelet-derived growth factor BB and interferon gamma.Front Med (Lausanne)2015;2:72
