Abstract
Hepatic fibrosis is the common pathological change that occurs due to increased synthesis and accumulation of extracellular matrix components. Chronic insult from hepatotoxicants leads to liver cirrhosis, which if not reversed timely using appropriate therapeutics, liver transplantation remains the only effective therapy. Often the disease further progresses into hepatic carcinoma. Although there is an increased advancement in understanding the pathological phenotypes of the disease, additional knowledge of the novel molecular signaling mechanisms involved in the disease progression would enable the development of efficacious therapeutics. Ephrin–Eph molecules belong to the largest family of receptor tyrosine kinases (RTKs) which are identified to play a crucial role in cellular migratory functions, during morphological and developmental stages. Additionally, they contribute to the growth of a multicellular organism as well as in pathological conditions like cancer, and diabetes. A wide spectrum of mechanistic studies has been performed on ephrin–Eph RTKs in various hepatic tissues under both normal and diseased conditions revealing their diverse roles in hepatic pathology. This systematic review summarizes the liver-specific ephrin–Eph RTK signaling mechanisms and recognizes them as druggable targets for mitigating hepatic pathology.
Graphical abstract
Similar content being viewed by others
References
Abd El Kader T, Kubota S, Janune D, Nishida T, Hattori T, Aoyama E, Perbal B, Kuboki T, Takigawa M (2013) Anti-fibrotic effect of CCN3 accompanied by altered gene expression profile of the CCN family. J Cell Commun Signal 7:11–18. https://doi.org/10.1007/s12079-012-0180-4
Alisi A, Da Sacco L, Bruscalupi G, Piemonte F, Panera N, De Vito R, Leoni S, Bottazzo GF, Masotti A, Nobili V (2011) Mirnome analysis reveals novel molecular determinants in the pathogenesis of the diet-induced nonalcoholic fatty liver disease. Lab Invest 9:283–293. https://doi.org/10.1038/labinvest.2010.166
Arcas A, Wilkinson DG, Nieto MA (2020) The evolutionary history of Ephs and Ephrins: toward multicellular organisms. Mol Biol Evol 37:379–394. https://doi.org/10.1093/molbev/msz222
Arthur A, Nguyen TM, Paton S, Klisuric A, Zannettino ACW, Gronthos S (2018) The osteoprogenitor-specific loss of ephrinB1 results in an osteoporotic phenotype affecting the balance between bone formation and resorption. Sci Rep 8:12756. https://doi.org/10.1038/s41598-018-31190-2
Azab F, Azab AK, Maiso P, Calimeri T, Flores L, Liu Y, Quang P, Roccaro AM, Sacco A, Ngo HT, Zhang Y (2013) Eph-B2/Ephrin-B2 interaction plays a major role in the adhesion and proliferation of Waldenstrom’s macroglobulinemia. Clin Cancer Res 18:91–105. https://doi.org/10.1158/1078-0432.CCR-11-0111
Bae HJ, Song JH, Noh JH, Kim JK, Jung KH, Eun JW, Xie HJ, Ryu JC, Ahn YM, Kim SY, Lee SH (2009) Low-frequency mutation of the Ephrin receptor A3 gene in hepatocellular carcinoma. Neoplasma 56:331–334. https://doi.org/10.4149/neo_2009_04_331
Bartley TD, Hunt RW, Welcher AA, Boyle WJ, Parker VP, Lindberg RA, Lu HS, Colombero AM, Elliott RL, Guthrie BA, Holst PL (1994) B61 is a ligand for the Eck receptor protein-tyrosine kinase. Nature 368:558–560. https://doi.org/10.1038/368558a0
Batlle E, Bacani J, Begthel H, Jonkheer S, Gregorieff A, van de Born M, Malats N, Sancho E, Boon E, Pawson T, Gallinger S, Pals S, Clevers H (2005) EphB receptor activity suppresses colorectal cancer progression. Nature 435:1126–1130. https://doi.org/10.1038/nature03626
Beckmann MP, Cerretti DP, Baum P, Vanden Bos T, James L, Farrah T, Kozlovsky C, Hollingsworth T, Shilling H, Maraskovsky E (1994) Molecular characterization of a family of ligands for Eph-related tyrosine kinase receptors. EMBO J 13:3757–3762. https://doi.org/10.1002/j.1460-2075.1994.tb06685.x
Benedict M, Zhang X (2017) Non-alcoholic fatty liver disease: an expanded review. World J Hepatol 9:715–732. https://doi.org/10.4254/wjh.v9.i16.715
Bochenek ML, Dickinson S, Astin JW, Adams RH, Nobes CD (2010) Ephrin-B2 regulates endothelial cell morphology and motility independently of Eph-receptor binding. J Cell Sci 123:1235–1246. https://doi.org/10.1242/jcs.061903
Chen G, Wang Y, Zhou M, Shi H, Yu Z, Zhu Y, Yu F (2010) EphA1 receptor silencing by small interfering RNA has antiangiogenic and antitumor efficacy in hepatocellular carcinoma. Oncol Rep 23:563–570. https://doi.org/10.3892/or_00000670
Chen Q, Song H, Liu C, Xu J, Wei C, Wang W, Han F (2020a) The interaction of EphA4 With PDGFR β regulates proliferation and neuronal differentiation of neural progenitor cells in vitro and promotes neurogenesis in vivo. Front Aging Neurosci 12:1–14. https://doi.org/10.3389/fnagi.2020.00007
Chen X, Zhang D, Wang Y, Chen K, Zhao L, Xu Y, Jiang H, Wang S (2020b) Synergistic antifibrotic effects of miR-451 with miR-185 partly by co-targeting EphB2 on hepatic stellate cells. Cell Death Dis 11:1–3. https://doi.org/10.1038/s41419-020-2613-y
Cheng HJ, Flanagan JG (1994) Identification and cloning of ELF-1, a developmentally expressed ligand for the Mek4 and Sek receptor tyrosine kinases. Cell 79:157–168. https://doi.org/10.1016/0092-8674(94)90408-1
Cui XD, Lee MJ, Kim JH, Hao PP, Liu L, Yu GR, Kim DG (2012) Activation of mammalian target of rapamycin complex 1 (mTORC1) and Raf/Pyk2 by growth factor-mediated Eph receptor 2 (EphA2) is required for cholangiocarcinoma growth and metastasis. Hepatol 1:2248–2260. https://doi.org/10.1002/hep.26253
Dalva MB, Takasu MA, Lin MZ, Shamah SM, Hu L, Gale NW, Greenberg ME (2000) EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103:945–956. https://doi.org/10.1016/s0092-8674(00)00197-5
Das A, Shergill U, Thakur L, Sinha S, Urrutia R, Mukhopadhyay D, Shah VH (2010) Ephrin B2/EphB4 pathway in hepatic stellate cells stimulates Erk-dependent VEGF production and sinusoidal endothelial cell recruitment. Am J Physiol Gastrointest Liver Physiol 298:908–915. https://doi.org/10.1152/ajpgi.00510.2009
Dill MT, Rothweiler S, Djonov V, Hlushchuk R, Tornillo L, Terracciano L, Meili-Butz S, Radtke F, Heim MH, Semela D (2012) Disruption of Notch1 induces vascular remodeling, intussusceptive angiogenesis, and angiosarcomas in livers of mice. Gastroenterol 142(4):967-977.e2. https://doi.org/10.1053/j.gastro.2011.12.052
El-Khoueiry A, Gitlitz B, Cole S, Tsao-Wei D, Goldkorn A, Quinn D, Lenz HJ, Nieva J, Dorff T, Oswald M, Berg J (2016) A first-in-human phase I study of sEphB4-HSA in patients with advanced solid tumors with expansion at the maximum tolerated dose (MTD) or recommended phase II dose (RP2D). Eur J Cancer 1(69):S11. https://doi.org/10.1016/s0959-8049(16)32623-5
Fan M, Liu Y, Xia F, Wang Z, Huang Y, Li J, Wang Z, Li X (2013) Increased expression of EphA2 and E–N cadherin switch in primary hepatocellular carcinoma. Tumori 99:689–696. https://doi.org/10.1177/030089161309900608
Ge YW, Liu ZQ, Sun ZY, Yu DG, Feng K, Zhu ZA, Mao YQ (2018) Titanium particle-mediated osteoclastogenesis may be attenuated via bidirectional ephrin-B2/Eph-B4 signaling in vitro. Int J Mol Med 42:2031–2041. https://doi.org/10.3892/ijmm.2018.3780
Gerhard GS, Legendre C, Still CD, Chu X, Petrick A, DiStefano JK (2018) Transcriptomic profiling of obesity-related nonalcoholic steatohepatitis reveals a core set of fibrosis-specific genes. J Endocr Soc 5:710–726. https://doi.org/10.1210/js.2018-00122
Giaginis C, Tsourouflis G, Zizi-Serbetzoglou A, Kouraklis G, Chatzopoulou E, Dimakopoulou K, Theocharis SE (2010) Clinical significance of ephrin (Eph)-A1, -A2, -a4, -a5 and -a7 receptors in pancreatic ductal adenocarcinoma. Pathol Oncol Res 16:267–276. https://doi.org/10.1007/s12253-009-9221-6
Hafner C, Schmitz G, Meyer S, Bataille F, Hau P, Langmann T, Dietmaier W, Landthaler M, Vogt T (2004) Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers. Clin Chem 50:490–499. https://doi.org/10.1373/clinchem.2003.026849
Himanen JP, Nikolov DB (2003) Eph signaling: a structural view. Trends Neurosci 26:46–51. https://doi.org/10.1016/s0166-2236(02)00005-x
Himanen J, Chumley MJ, Lackmann M, Li C, Barton WA, Jeffrey PD, Vearing C, Geleick D, Feldheim DA, Boyd AW, Henkemeyer M (2004) Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci 7:501–509. https://doi.org/10.1038/nn1237
Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F (1987) A novel putative tyrosine kinase receptor encoded by the Eph gene. Science 238:1717–1720. https://doi.org/10.1126/science.2825356
Huang G, Brigstock DR (2012) Regulation of hepatic stellate cells by connective tissue growth factor. Front Biosci (landmark Ed) 17:2495–2507. https://doi.org/10.2741/4067
Husain A, Chiu YT, Sze KM, Ho DW, Tsui YM, Suarez EM, Zhang VX, Chan LK, Lee E, Lee JM, Cheung TT (2022) Ephrin-A3/EphA2 axis regulates cellular metabolic plasticity to enhance cancer stemness in hypoxic hepatocellular carcinoma. J Hepatol 8278:125–128. https://doi.org/10.1016/j.jhep.2022.02.018
Ibrahim SH, Hirsova P, Gores GJ (2018) Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation. Gut 67:963–972. https://doi.org/10.1136/gutjnl-2017-315691
Iida H, Honda M, Kawai HF, Yamashita T, Shirota Y, Wang BC, Miao H, Kaneko S (2005) Ephrin-A1 expression contributes to the malignant characteristics of α-fetoprotein producing hepatocellular carcinoma. Gut 54:843–851. https://doi.org/10.1136/gut.2004.049486
Jain R, Jain D, Liu Q, Bartosinska B, Wang J, Schumann D, Kauschke SG, Eickelmann P, Piemonte L, Gray NS, Lammert E (2013) Pharmacological inhibition of Eph receptors enhances glucose-stimulated insulin secretion from mouse and human pancreatic islets. Diabetologia 56:1350–1355. https://doi.org/10.1007/s00125-013-2877-1
Jia Q, Dong Q, Qin L (2016) CCN: core regulatory proteins in the microenvironment that affect the metastasis of hepatocellular carcinoma. Oncotarget 7:1203–1214. https://doi.org/10.18632/oncotarget.6209
Kao T, Kania A (2011) Ephrin-mediated cis -attenuation of Eph receptor signaling is essential for spinal motor axon guidance. Neuron 71:76–91. https://doi.org/10.1016/j.neuron.2011.05.031
Khansaard W, Techasen A, Namwat N, Yongvanit P, Khuntikeo N, Puapairoj A, Loilome W (2014) Increased EphB2 expression predicts cholangiocarcinoma metastasis. Tumor Biol 35:10031–10041. https://doi.org/10.1007/s13277-014-2295-0
Kim KH, Cheng N, Lau LF (2022) Cellular communication network factor 1-stimulated liver macrophage efferocytosis drives hepatic stellate cell activation and liver fibrosis. Hepatol Commun 6:2798–2811. https://doi.org/10.1002/hep4.2057
Kullander K, Klein R (2002) Mechanisms and functions of Eph and ephrin signaling. Nat Commun Mol Cell Biol 3:475–486. https://doi.org/10.1038/nrm856
Leung HW, Leung CON, Lau EY et al (2021) EPHB2 activates β-catenin to enhance cancer stem cell properties and drive sorafenib resistance in hepatocellular carcinoma. Cancer Res 81:3229–3240. https://doi.org/10.1158/0008-5472.can-21-0184
Li R, Zhang D, Han Y, Chen K, Guo W, Chen Y, Wang S (2023) Neddylation of EphB1 regulates its activity and associates with liver fibrosis. Int J Mol Sci 24:3415. https://doi.org/10.3390/ijms24043415
Lim YS, McLaughlin T, Sung TC, Santiago A, Lee KF, O’Leary DD (2008) p75NTR mediates ephrin-A reverse signaling required for axon repulsion and mapping. Neuron 59:746–758. https://doi.org/10.1016/j.neuron.2008.07.032
Liu S, Gong J, Morishita A, Nomura T, Miyoshi H, Tani J, Kato K, Yoneyama H, Deguchi A, Mori H, Mimura S (2011) Use of protein array technology to investigate receptor tyrosine kinases activated in hepatocellular carcinoma. Exp Therap Med 2:399–403. https://doi.org/10.3892/etm.2011.215
Liu C, Huang H, Wang C, Kong Y, Zhang H (2014) Involvement of ephrin receptor A4 in pancreatic cancer cell motility and invasion. Oncol Lett 7:2165–2169. https://doi.org/10.3892/ol.2014.2011
Liu J, Ji Y, Ai H, Ning B, Zhao J, Zhang Y, Dun G (2016) Liver shear-wave velocity and serum fibrosis markers to diagnose hepatic fibrosis in patients with chronic viral hepatitis B. Kor J Radiol 17:396–404. https://doi.org/10.3348/kjr.2016.17.3.396
Manning G, Plowman GD, Hunter T, Sudarsanam S (2002) Evolution of protein kinase signaling from yeast to man. Trends Biochem Sci 27:514–520. https://doi.org/10.1016/s0968-0004(02)02179-5
Mateo-Lozano S, Bazzocco S, Rodrigues P, Mazzolini R, Andretta E, Dopeso H, Fernández Y, Del Llano E, Bilic J, Suárez-López L, Macaya I (2017) Loss of the EPH receptor B6 contributes to colorectal cancer metastasis. Sci Rep 7:43702. https://doi.org/10.1038/srep43702
Mimche PN, Brady LM, Bray CF, Lee CM, Thapa M, King TP, Quicke K, McDermott CD, Mimche SM, Grakoui A, Morgan ET (2015) The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice. Hepatol 62:900–914. https://doi.org/10.1002/hep.27792
Mimche PN, Lee CM, Mimche SM, Thapa M, Grakoui A, Henkemeyer M, Lamb TJ (2018) EphB2 receptor tyrosine kinase promotes hepatic fibrogenesis in mice via activation of hepatic stellate cells. Sci Rep 8:1–14. https://doi.org/10.1038/s41598-018-20926-9
Moylan CA, Pang H, Dellinger A, Garrett ME, Guy CD, Murphy SK, Ashley-Loch AE, Choi SS, Michelotti GA, Hampton DD (2014) Hepatic gene expression profiles differentiate pre-symptomatic patients with mild versus severe nonalcoholic fatty liver disease. Hepatol 59:471–482. https://doi.org/10.1002/hep.26661
Mukai M, Suruga N, Saeki N, Ogawa K (2017) EphA receptors and ephrin-A ligands are upregulated by monocytic differentiation/maturation and promote cell adhesion and protrusion formation in HL60 monocytes. BMC Cell Biol 18:1–20. https://doi.org/10.1186/s12860-017-0144-x
Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, Swain MG, Congly SE, Kaplan GG, Shaheen AA (2022) The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 7:851–861. https://doi.org/10.1016/S2468-1253(22)00165-0
Sawai Y, Tamura S, Fukui K, Ito N, Imanaka K, Saeki A, Sauda S, Kiso S, Matsuzawa Y (2003) Expression of ephrin-B1 in hepatocellular carcinoma: possible involvement in neovascularization. J Hepatol 39:991–996. https://doi.org/10.1016/S0168-8278(03)00498-7
Sayiner M, Koenig A, Henry L, Younossi ZM (2016) Epidemiology of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the United States and rest of the world. Clin Liver Dis 20:205–214. https://doi.org/10.1016/j.cld.2015.10.001
Semela D, Das A, Langer D, Kang N, Leof E, Shah V (2008) Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function. Gastroenterol 135:671–679. https://doi.org/10.1053/j.gastro.2008.04.010
Sheng Y, Wei J, Zhang Y, Gao X, Wang Z, Yang J, Yan S, Zhu Y, Zhang Z, Xu D, Wang C (2019) Mutated EPHA2 is a target for combating lymphatic metastasis in intrahepatic cholangiocarcinoma. Int J Can 144:2440–2452. https://doi.org/10.1002/ijc.31979
Singh DR, Ahmed F, Paul MD, Gedam M, Pasquale EB, Hristova K (2017) The SAM domain inhibits EphA2 interactions in the plasma membrane. Biochimica Et Biophysica Acta (BBA)-Mol Cell Res 1864:31–38. https://doi.org/10.1016/j.bbamcr.2016.10.011
Srivastava A, Shukla V, Tiwari D, Gupta J, Kumar S, Kumar A (2018) Targeted therapy of chronic liver diseases with the inhibitors of angiogenesis. Biomed Pharmacother 105:256–266. https://doi.org/10.1016/j.biopha.2018.05.102
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660
Tabrizian P, Jibara G, Hechtman JF, Franssen B, Labow DM, Schwartz ME, Thung SN, Sarpel U (2015) Outcomes following resection of intrahepatic cholangiocarcinoma. HPB 17:344–351. https://doi.org/10.1111/hpb.12359
Tazaki Y, Sugitani K, Ogai K, Kobayashi I, Kawasaki H, Aoyama T, Suzuki N, Tabuchi Y, Hattori A, Kitamura KI (2018) RANKL, Ephrin–Eph, and Wnt10b are key intercellular communication molecules regulating bone remodeling in autologous transplanted goldfish scales. Comp Biochem Physiol Part A Mol Integrative Physiol 225:46–58. https://doi.org/10.1016/j.cbpa.2018.06.011
Teng S, Palmieri A, Maita I, Zheng C, Das G, Park J, Zhou R, Alder J, Thakker-Varia S (2019) Inhibition of EphA/Ephrin-A signaling using genetic and pharmacologic approaches improve recovery following traumatic brain injury in mice. Brain Inj 33:1385–41401. https://doi.org/10.1080/02699052.2019.1641622
Tong Z, Chen R, Alt DS, Kemper S, Perbal B, Brigstock DR (2009) Susceptibility to liver fibrosis in mice expressing a connective tissue growth factor transgene in hepatocytes. Hepatology 50(3):939–947. https://doi.org/10.1002/hep.23102
Wang TH, Ng KF, Sen YT, Wang YL, Liang KH, Yeh CT, Chen TC (2012) Peritumoral small EphrinA5 isoform level predicts the postoperative survival in hepatocellular carcinoma. PLoS ONE 7:1–11. https://doi.org/10.1371/journal.pone.0041749
Wang Y, Li Q, Zheng Y, Li G, Liu W (2016a) Systematic biochemical characterization of the SAM domains in Eph receptor family from Mus Musculus. Biochem Biophys Res Comm 473:1281–1287. https://doi.org/10.1016/j.bbrc.2016.04.059
Wang Y, Yu H, Shan Y, Tao C, Wu F, Yu Z, Guo P, Huang J, Li J, Zhu Q, Yu F (2016b) EphA1 activation promotes the homing of endothelial progenitor cells to hepatocellular carcinoma for tumor neovascularization through the SDF-1/CXCR4 signaling pathway. J Exp Clin Cancer Res 35:1–15. https://doi.org/10.1186/s13046-016-0339-6
Wang X, Zhang M, Ping F, Liu H, Sun J, Wang Y, Shen A, Ding J, Geng M (2019) Identification and therapeutic intervention of coactivated anaplastic lymphoma kinase, fibroblast growth factor receptor 2, and ephrin type-A receptor 5 kinases in hepatocellular carcinoma. Hepatol 69:573–586. https://doi.org/10.1002/hep.29792
Wang H, Hou W, Perera A, Bettler C, Beach JR, Ding X, Li J, Denning MF, Dhanarajan A, Cotler SJ, Joyce C (2021) Targeting EphA2 suppresses hepatocellular carcinoma initiation and progression by dual inhibition of JAK1/STAT3 and AKT signaling. Cell Rep 34:108765. https://doi.org/10.1016/j.celrep.2021.108765
Wu Z, Liu R, Xiong L, Miao X, Li D, Zou Q, Yuan Y, Yang Z (2020) Prognostic and clinicopathological significance of EphB3 and dysadherin expression in extrahepatic cholangiocarcinoma. Cancer Manag Res 12:221–232. https://doi.org/10.2147/CMAR.S232278
Xiao Y, Batmanov K, Hu W, Zhu K, Tom AY, Guan D, Jiang C, Cheng L, McCright SJ, Yang EC, Lanza MR, Liu Y, Hill DA, Lazar MA (2023) Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Sci Transl Med 15:9653. https://doi.org/10.1126/scitranslmed.adc9653
Xu K, Tzvetkova-Robev D, Xu Y, Goldgur Y, Chan YP, Himanen JP, Nikolov DB (2013) Insights into Eph receptor tyrosine kinase activation from crystal structures of the EphA4 ectodomain and its complex with ephrin-A5. Proc Nat Acad Sci 110:14634–14639. https://doi.org/10.1073/pnas.1311000110
Yamaguchi S, Tatsumi T, Takehara T, Sasakawa A, Yamamoto M, Kohga K, Miyagi T, Kanto T, Hiramastu N, Akagi T, Akashi M, Hayashi N (2010) EphA2-derived peptide vaccine with amphiphilic poly(gamma-glutamic acid) nanoparticles elicits an anti-tumor effect against mouse liver tumor. Cancer Immunol Immunother 59:759–767. https://doi.org/10.1007/s00262-009-0796-2
Yang P, Yuan W, He J, Wang J, Yu L, Jin X, Hu Y, Liao M, Chen Z, Zhang Y (2009) Overexpression of EphA2, MMP-9, and MVD-CD34 in hepatocellular carcinoma: implications for tumor progression and prognosis. Hepatol Res 39:1169–1177. https://doi.org/10.1111/j.1872-034X.2009.00563.x
Yeger H, Perbal B (2016) CCN family of proteins: critical modulators of the tumor cell microenvironment. J Cell Commun Signal 10:229–240. https://doi.org/10.1007/s12079-016-0346-6
Yin L, Cai Z, Zhu B, Xu C (2018) Identification of key pathways and genes in the dynamic progression of HCC based on WGCNA. Genes (basel) 9:92. https://doi.org/10.3390/genes9020092
Yoon J, Hwang YS, Lee M, Sun J, Cho HJ, Knapik L, Daar IO (2018) TBC1d24-ephrinB2 interaction regulates contact inhibition of locomotion in neural crest cell migration. Nat Comm 9:3491. https://doi.org/10.1038/s41467-018-05924-9
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2016) Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatol 64:73–84. https://doi.org/10.1002/hep.28431
Acknowledgements
Manuscript Communication number: IICT/Pubs./2022/171.
Funding
AD acknowledges the funding provided by the Council of Scientific and Industrial Research (CSIR), Ministry of Science & Technology, Government of India for Niche Creating High Science Project MLP-0052 and Focused Basic Research MLP-0277 under the Health Care Theme. The fellowship provided by UGC-JRF/SRF to SM is gratefully acknowledged.
Author information
Authors and Affiliations
Contributions
AD—Study concept and design; drafting of the manuscript; critical revision of the manuscript; obtained funding; study supervision. SM & PD—Literature search through databases; figures and tables; drafting of the manuscript; critical revision of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Mekala, S., Dugam, P. & Das, A. Ephrin–Eph receptor tyrosine kinases for potential therapeutics against hepatic pathologies. J. Cell Commun. Signal. 17, 549–561 (2023). https://doi.org/10.1007/s12079-023-00750-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12079-023-00750-1