Pathogenesis from Inflammation to Cancer in NASH-Derived HCC

References

• Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi:10.3322/caac.21660
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi:10.1016/j.cell.2011.02.013
   PubMed Web of Science ®Google Scholar
• Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–545. doi:10.1016/S0140-6736(00)04046-0
   PubMed Web of Science ®Google Scholar
• Hibino S, Kawazoe T, Kasahara H, et al. Inflammation-induced tumorigenesis and metastasis. Int J Mol Sci. 2021;22(11):5421. doi:10.3390/ijms22115421
   PubMed Web of Science ®Google Scholar
• Xu W, Yu J, Wong VW. Mechanism and prediction of HCC development in HBV infection. Best Pract Res Clin Gastroenterol. 2017;31(3):291–298. doi:10.1016/j.bpg.2017.04.011
   PubMed Web of Science ®Google Scholar
• Gawrieh S, Dakhoul L, Miller E, et al. Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study. Aliment Pharmacol Ther. 2019;50(7):809–821. doi:10.1111/apt.15464
   PubMed Web of Science ®Google Scholar
• Stine JG, Wentworth BJ, Zimmet A, et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment Pharmacol Ther. 2018;48(7):696–703. doi:10.1111/apt.14937
   PubMed Web of Science ®Google Scholar
• Mittal S, El-Serag HB, Sada YH, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2016;14(1):124–31.e1. doi:10.1016/j.cgh.2015.07.019
   PubMed Web of Science ®Google Scholar
• Pais R, Fartoux L, Goumard C, et al. Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period. Aliment Pharmacol Ther. 2017;46(9):856–863. doi:10.1111/apt.14261
   PubMed Web of Science ®Google Scholar
• Ioannou GN. Epidemiology and risk-stratification of NAFLD-associated HCC. J Hepatol. 2021;75(6):1476–1484. doi:10.1016/j.jhep.2021.08.012
   PubMed Web of Science ®Google Scholar
• Younossi Z, Stepanova M, Ong JP, et al. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin Gastroenterol Hepatol. 2019;17(4):748–755.e3. doi:10.1016/j.cgh.2018.05.057
   PubMed Web of Science ®Google Scholar
• Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol. 2019;16(7):411–428. doi:10.1038/s41575-019-0145-7
   PubMed Web of Science ®Google Scholar
• Michelotti A, de Scordilli M, Palmero L, et al. NAFLD-related hepatocarcinoma: the malignant side of metabolic syndrome. Cells. 2021;10(8):2034. doi:10.3390/cells10082034
   PubMed Web of Science ®Google Scholar
• Machado MV, Diehl AM. Pathogenesis of Nonalcoholic Steatohepatitis. Gastroenterology. 2016;150(8):1769–1777. doi:10.1053/j.gastro.2016.02.066
   PubMed Web of Science ®Google Scholar
• Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343–1351. doi:10.1172/JCI23621
   PubMed Web of Science ®Google Scholar
• Cortés-Rojo C, Vargas-Vargas MA, Olmos-Orizaba BE, Rodríguez-Orozco AR, Calderón-Cortés E. Interplay between NADH oxidation by complex I, glutathione redox state and sirtuin-3, and its role in the development of insulin resistance. Biochim Biophys Acta Mol Basis Dis. 2020;1866(8):165801. doi:10.1016/j.bbadis.2020.165801.
   PubMed Web of Science ®Google Scholar
• Smith GI, Shankaran M, Yoshino M, et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest. 2020;130(3):1453–1460. doi:10.1172/JCI134165.
   PubMed Web of Science ®Google Scholar
• Singh S, Anshita D, Ravichandiran V. MCP-1: function, regulation, and involvement in disease. Int Immunopharmacol. 2021;101(Pt B):107598. doi:10.1016/j.intimp.2021.107598
   PubMed Web of Science ®Google Scholar
• Khan RS, Bril F, Cusi K, Newsome PN. Modulation of insulin resistance in nonalcoholic fatty liver disease. Hepatology. 2019;70(2):711–724. doi:10.1002/hep.30429
   PubMed Web of Science ®Google Scholar
• Eckstein SS, Weigert C, Lehmann R. Divergent roles of IRS (Insulin Receptor Substrate) 1 and 2 in liver and skeletal muscle. Curr Med Chem. 2017;24(17):1827–1852. doi:10.2174/0929867324666170426142826
   PubMed Web of Science ®Google Scholar
• Fujii H, Kawada N; Japan Study Group Of Nafld Jsg-Nafld. The role of insulin resistance and diabetes in nonalcoholic fatty liver disease. Int J Mol Sci. 2020;21(11):3863. doi:10.3390/ijms21113863
   PubMed Web of Science ®Google Scholar
• Jin D, Sun J, Huang J, et al. TNF-α reduces g0s2 expression and stimulates lipolysis through PPAR-γ inhibition in 3T3-L1 adipocytes. Cytokine. 2014;69(2):196–205. doi:10.1016/j.cyto.2014.06.005
   PubMed Web of Science ®Google Scholar
• Skat-Rørdam J, Højland Ipsen D, Lykkesfeldt J, Tveden-Nyborg P. A role of peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease. Basic Clin Pharmacol Toxicol. 2019;124(5):528–537. doi:10.1111/bcpt.13190
   PubMed Web of Science ®Google Scholar
• Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol. 2018;68(2):280–295. doi:10.1016/j.jhep.2017.11.014
   PubMed Web of Science ®Google Scholar
• Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci. 2018;75(18):3313–3327. doi:10.1007/s00018-018-2860-6
   PubMed Web of Science ®Google Scholar
• Mansouri A, Gattolliat CH, Asselah T. Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology. 2018;155(3):629–647. doi:10.1053/j.gastro.2018.06.083
   PubMed Web of Science ®Google Scholar
• Arroyave-Ospina JC, Wu Z, Geng Y, Moshage H. Role of oxidative stress in the pathogenesis of non-alcoholic fatty liver disease: implications for prevention and therapy. Antioxidants. 2021;10(2):174. doi:10.3390/antiox10020174
   Web of Science ®Google Scholar
• Zhang Z, Zhang L, Zhou L, Lei Y, Zhang Y, Huang C. Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress. Redox Biol. 2019;25:101047. doi:10.1016/j.redox.2018.11.005
   PubMed Web of Science ®Google Scholar
• Henkel A, Green RM. The unfolded protein response in fatty liver disease. Semin Liver Dis. 2013;33(4):321–329. doi:10.1055/s-0033-1358522
   PubMed Web of Science ®Google Scholar
• Lebeaupin C, Vallée D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018;69(4):927–947. doi:10.1016/j.jhep.2018.06.008
   PubMed Web of Science ®Google Scholar
• Vallée D, Blanc M, Lebeaupin C, Bailly-Maitre B. La réponse au stress du réticulum endoplasmique dans la physiopathologie des maladies chroniques du foie [Endoplasmic reticulum stress response and pathogenesis of non-alcoholic steatohepatitis]. Med Sci. 2020;36(2):119–129. French. doi:10.1051/medsci/2020008
   Web of Science ®Google Scholar
• Flessa CM, Kyrou I, Nasiri-Ansari N, et al. Endoplasmic reticulum stress and autophagy in the pathogenesis of Non-alcoholic Fatty Liver Disease (NAFLD): current evidence and perspectives. Curr Obes Rep. 2021;10(2):134–161. doi:10.1007/s13679-021-00431-3
   PubMed Web of Science ®Google Scholar
• Kubes P, Jenne C. Immune responses in the liver. Annu Rev Immunol. 2018;36(1):247–277. doi:10.1146/annurev-immunol-051116-052415
   PubMed Web of Science ®Google Scholar
• Zheng M, Tian Z. Liver-mediated adaptive immune tolerance. Front Immunol. 2019;10:2525. doi:10.3389/fimmu.2019.02525
   PubMed Web of Science ®Google Scholar
• Koo SY, Park EJ, Lee CW. Immunological distinctions between nonalcoholic steatohepatitis and hepatocellular carcinoma. Exp Mol Med. 2020;52(8):1209–1219. doi:10.1038/s12276-020-0480-3
   PubMed Web of Science ®Google Scholar
• Torre P, Motta BM, Sciorio R, Masarone M, Inflammation PM. Fibrogenesis in MAFLD: role of the hepatic immune system. Front Med. 2021;8:781567. doi:10.3389/fmed.2021.781567
   Web of Science ®Google Scholar
• Roohani S, Tacke F. Liver injury and the macrophage issue: molecular and mechanistic facts and their clinical relevance. Int J Mol Sci. 2021;22(14):7249. doi:10.3390/ijms22147249
   PubMed Web of Science ®Google Scholar
• Xu L, Liu W, Bai F, et al. Hepatic macrophage as a key player in fatty liver disease. Front Immunol. 2021;12:708978. doi:10.3389/fimmu.2021.708978
   PubMed Web of Science ®Google Scholar
• Rosso C, Kazankov K, Younes R, et al. Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease. J Hepatol. 2019;71(5):1012–1021. doi:10.1016/j.jhep.2019.06.031
   PubMed Web of Science ®Google Scholar
• Grunhut J, Wang W, Aykut B, Gakhal I, Torres-Hernandez A, Miller G. Macrophages in nonalcoholic steatohepatitis: friend or foe? Eur Med J Hepatol. 2018;6(1):100–109.
   PubMedGoogle Scholar
• Mihm S. Danger-Associated Molecular Patterns (DAMPs): molecular triggers for sterile inflammation in the liver. Int J Mol Sci. 2018;19(10):3104. doi:10.3390/ijms19103104
   PubMed Web of Science ®Google Scholar
• Dou L, Shi X, He X, Gao Y. Macrophage phenotype and function in liver disorder. Front Immunol. 2020;10:3112. doi:10.3389/fimmu.2019.03112
   PubMed Web of Science ®Google Scholar
• Li H, Zhou Y, Wang H, et al. Crosstalk between liver macrophages and surrounding cells in nonalcoholic steatohepatitis. Front Immunol. 2020;11:1169. doi:10.3389/fimmu.2020.01169
   PubMed Web of Science ®Google Scholar
• Wenfeng Z, Yakun W, Di M, Jianping G, Chuanxin W, Chun H. Kupffer cells: increasingly significant role in nonalcoholic fatty liver disease. Ann Hepatol. 2014;13(5):489–495. doi:10.1016/S1665-2681(19)31247-5
   PubMed Web of Science ®Google Scholar
• Bieghs V, Trautwein C. The innate immune response during liver inflammation and metabolic disease. Trends Immunol. 2013;34(9):446–452. doi:10.1016/j.it.2013.04.005
   PubMed Web of Science ®Google Scholar
• Zhang WJ, Chen SJ, Zhou SC, Wu SZ, Wang H. Inflammasomes and Fibrosis. Front Immunol. 2021;12:643149. doi:10.3389/fimmu.2021.643149
   PubMed Web of Science ®Google Scholar
• Wan J, Benkdane M, Teixeira-Clerc F, et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology. 2014;59(1):130–142. doi:10.1002/hep.26607
   PubMed Web of Science ®Google Scholar
• Lis-López L, Bauset C, Seco-Cervera M, Cosín-Roger J. Is the macrophage phenotype determinant for fibrosis development? Biomedicines. 2021;9(12):1747. doi:10.3390/biomedicines9121747
   PubMed Web of Science ®Google Scholar
• Cheng D, Chai J, Wang H, Fu L, Peng S, Ni X. Hepatic macrophages: key players in the development and progression of liver fibrosis. Liver Int. 2021;41(10):2279–2294. doi:10.1111/liv.14940
   PubMed Web of Science ®Google Scholar
• Sufleţel RT, Melincovici CS, Gheban BA, Toader Z, Mihu CM. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. Rom J Morphol Embryol. 2020;61(3):615–642. doi:10.47162/RJME.61.3.01
   PubMed Web of Science ®Google Scholar
• Kamm DR, McCommis KS. Hepatic stellate cells in physiology and pathology. J Physiol. 2022;600(8):1825–1837. doi:10.1113/JP281061
   PubMed Web of Science ®Google Scholar
• Zisser A, Ipsen DH, Tveden-Nyborg P. Hepatic stellate cell activation and inactivation in NASH-fibrosis-roles as putative treatment targets? Biomedicines. 2021;9(4):365. doi:10.3390/biomedicines9040365
   PubMed Web of Science ®Google Scholar
• Schwabe RF, Tabas I, Pajvani UB. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology. 2020;158(7):1913–1928. doi:10.1053/j.gastro.2019.11.311
   PubMed Web of Science ®Google Scholar
• Matsuda M, Seki E. Hepatic stellate cell-macrophage crosstalk in liver fibrosis and carcinogenesis. Semin Liver Dis. 2020;40(3):307–320. doi:10.1055/s-0040-1708876
   PubMed Web of Science ®Google Scholar
• Li T, Yang Y, Song H, et al. Activated NK cells kill hepatic stellate cells via p38/PI3K signaling in a TRAIL-involved degranulation manner. J Leukoc Biol. 2019;105(4):695–704. doi:10.1002/JLB.2A0118-031RR
   PubMed Web of Science ®Google Scholar
• Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology. 2006;130(2):435–452. doi:10.1053/j.gastro.2005.10.055
   PubMed Web of Science ®Google Scholar
• Caligiuri A, Gentilini A, Pastore M, Gitto S, Marra F. Cellular and molecular mechanisms underlying liver fibrosis regression. Cells. 2021;10(10):2759. doi:10.3390/cells10102759
   PubMed Web of Science ®Google Scholar
• Krizhanovsky V, Yon M, Dickins RA, et al. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008;134(4):657–667. doi:10.1016/j.cell.2008.06.049
   PubMed Web of Science ®Google Scholar
• Stiglund N, Strand K, Cornillet M, et al. Retained NK cell phenotype and functionality in non-alcoholic fatty liver disease. Front Immunol. 2019;10:1255. doi:10.3389/fimmu.2019.01255
   PubMed Web of Science ®Google Scholar
• Narayanan S, Surette FA, Hahn YS. The immune landscape in nonalcoholic steatohepatitis. Immune Netw. 2016;16(3):147–158. doi:10.4110/in.2016.16.3.147
   PubMed Web of Science ®Google Scholar
• Audiger C, Rahman MJ, Yun TJ, Tarbell KV, Lesage S. The importance of dendritic cells in maintaining immune tolerance. J Immunol. 2017;198(6):2223–2231. doi:10.4049/jimmunol.1601629
   PubMed Web of Science ®Google Scholar
• Méndez-Sánchez N, Córdova-Gallardo J, Barranco-Fragoso B, Eslam M. Hepatic dendritic cells in the development and progression of metabolic steatohepatitis. Front Immunol. 2021;12:641240. doi:10.3389/fimmu.2021.641240
   PubMed Web of Science ®Google Scholar
• Almeda-Valdes P, Aguilar Olivos NE, Barranco-Fragoso B, Uribe M, Méndez-Sánchez N. The role of dendritic cells in fibrosis progression in nonalcoholic fatty liver disease. Biomed Res Int. 2015;2015:768071. doi:10.1155/2015/768071
   PubMed Web of Science ®Google Scholar
• Henning JR, Graffeo CS, Rehman A, et al. Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice. Hepatology. 2013;58(2):589–602. doi:10.1002/hep.26267
   PubMed Web of Science ®Google Scholar
• Xu Y, Tang X, Yang M, et al. Interleukin 10 gene-modified bone marrow-derived dendritic cells attenuate liver fibrosis in mice by inducing regulatory T cells and inhibiting the TGF-β/smad signaling pathway. Mediators Inflamm. 2019;2019:4652596. doi:10.1155/2019/4652596
   PubMed Web of Science ®Google Scholar
• Bamboat ZM, Ocuin LM, Balachandran VP, Obaid H, Plitas G, DeMatteo RP. Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion. J Clin Invest. 2010;120(2):559–569. doi:10.1172/JCI40008
   PubMed Web of Science ®Google Scholar
• Bhattacharjee J, Kumar JM, Arindkar S, et al. Role of immunodeficient animal models in the development of fructose induced NAFLD. J Nutr Biochem. 2014;25(2):219–226. doi:10.1016/j.jnutbio.2013.10.010
   PubMed Web of Science ®Google Scholar
• Ruterbusch M, Pruner KB, Shehata L, Pepper M. In vivo CD4+ T Cell differentiation and function: revisiting the Th1/Th2 paradigm. Annu Rev Immunol. 2020;38:705–725. doi:10.1146/annurev-immunol-103019-085803
   PubMed Web of Science ®Google Scholar
• Li N, Yamamoto G, Fuji H, Kisseleva T. Interleukin-17 in liver disease pathogenesis. Semin Liver Dis. 2021;41(4):507–515. doi:10.1055/s-0041-1730926
   PubMed Web of Science ®Google Scholar
• Rolla S, Alchera E, Imarisio C, et al. The balance between IL-17 and IL-22 produced by liver-infiltrating T-helper cells critically controls NASH development in mice. Clin Sci. 2016;130(3):193–203. doi:10.1042/CS20150405
   Web of Science ®Google Scholar
• Zai W, Chen W, Liu H, Ju D. Therapeutic opportunities of IL-22 in non-alcoholic fatty liver disease: from molecular mechanisms to clinical applications. Biomedicines. 2021;9(12):1912. doi:10.3390/biomedicines9121912
   PubMed Web of Science ®Google Scholar
• Zheng Q, Martin RC, Shi X, et al. Lack of FGF21 promotes NASH-HCC transition via hepatocyte-TLR4-IL-17A signaling. Theranostics. 2020;10(22):9923–9936. doi:10.7150/thno.45988
   PubMed Web of Science ®Google Scholar
• Chehimi M, Vidal H, Eljaafari A. Pathogenic role of IL-17-producing immune cells in obesity, and related inflammatory diseases. J Clin Med. 2017;6(7):68. doi:10.3390/jcm6070068
   PubMed Web of Science ®Google Scholar
• Van Herck MA, Weyler J, Kwanten WJ, et al. The differential roles of T cells in non-alcoholic fatty liver disease and obesity. Front Immunol. 2019;10:82. doi:10.3389/fimmu.2019.00082
   PubMed Web of Science ®Google Scholar
• Ramani K, Biswas PS. Interleukin-17: friend or foe in organ fibrosis. Cytokine. 2019;120:282–288. doi:10.1016/j.cyto.2018.11.003
   PubMed Web of Science ®Google Scholar
• Zhang S, Gang X, Yang S, et al. The alterations in and the role of the Th17/Treg Balance in metabolic diseases. Front Immunol. 2021;12:678355. doi:10.3389/fimmu.2021.678355
   PubMed Web of Science ®Google Scholar
• He B, Wu L, Xie W, et al. The imbalance of Th17/Treg cells is involved in the progression of nonalcoholic fatty liver disease in mice. BMC Immunol. 2017;18(1):33. doi:10.1186/s12865-017-0215-y
   PubMed Web of Science ®Google Scholar
• Ma C, Kesarwala AH, Eggert T, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531(7593):253–257. doi:10.1038/nature16969
   PubMed Web of Science ®Google Scholar
• Bakiri L, Hamacher R, Graña O, et al. Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation. J Exp Med. 2017;214(5):1387–1409. doi:10.1084/jem.20160935
   PubMed Web of Science ®Google Scholar
• Krijgsman D, Hokland M, Kuppen PJK. The role of natural killer T cells in cancer-A phenotypical and functional approach. Front Immunol. 2018;9:367. doi:10.3389/fimmu.2018.00367
   PubMed Web of Science ®Google Scholar
• Crosby CM, Kronenberg M. Tissue-specific functions of invariant natural killer T cells. Nat Rev Immunol. 2018;18(9):559–574. doi:10.1038/s41577-018-0034-2
   PubMed Web of Science ®Google Scholar
• Kumar V. NKT-cell subsets: promoters and protectors in inflammatory liver disease. J Hepatol. 2013;59(3):618–620. doi:10.1016/j.jhep.2013.02.032
   PubMed Web of Science ®Google Scholar
• Maricic I, Sheng H, Marrero I, et al. Inhibition of type I natural killer T cells by retinoids or following sulfatide-mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice. Hepatology. 2015;61(4):1357–1369. doi:10.1002/hep.27632
   PubMed Web of Science ®Google Scholar
• Bandyopadhyay K, Marrero I, Kumar V. NKT cell subsets as key participants in liver physiology and pathology. Cell Mol Immunol. 2016;13(3):337–346. doi:10.1038/cmi.2015.115
   PubMed Web of Science ®Google Scholar
• Nilsson J, Hörnberg M, Schmidt-Christensen A, et al. NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis. Sci Rep. 2020;10(1):21778. doi:10.1038/s41598-020-78688-2
   PubMed Web of Science ®Google Scholar
• Bhattacharjee J, Kirby M, Softic S, et al. Hepatic natural killer T-cell and CD8+ T-cell signatures in mice with nonalcoholic steatohepatitis. Hepatol Commun. 2017;1(4):299–310. doi:10.1002/hep4.1041
   PubMed Web of Science ®Google Scholar
• Dudek M, Pfister D, Donakonda S, et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature. 2021;592(7854):444–449. doi:10.1038/s41586-021-03233-8
   PubMed Web of Science ®Google Scholar
• Breuer DA, Pacheco MC, Washington MK, Montgomery SA, Hasty AH, Kennedy AJ. CD8+ T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol. 2020;318(2):G211–G224. doi:10.1152/ajpgi.00040.2019
   PubMed Web of Science ®Google Scholar
• Hirsova P, Bamidele AO, Wang H, Povero D, Revelo XS. Emerging roles of T cells in the pathogenesis of nonalcoholic steatohepatitis and hepatocellular carcinoma. Front Endocrinol. 2021;12:760860. doi:10.3389/fendo.2021.760860
   PubMed Web of Science ®Google Scholar
• Wolf MJ, Adili A, Piotrowitz K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 2014;26(4):549–564. doi:10.1016/j.ccell.2014.09.003
   PubMed Web of Science ®Google Scholar
• Barrow F, Khan S, Wang H, Revelo XS. The emerging role of B cells in the pathogenesis of NAFLD. Hepatology. 2021;74(4):2277–2286. doi:10.1002/hep.31889
   PubMed Web of Science ®Google Scholar
• Nakamura Y, Abe M, Kawasaki K, et al. Depletion of B cell-activating factor attenuates hepatic fat accumulation in a murine model of nonalcoholic fatty liver disease. Sci Rep. 2019;9(1):977. doi:10.1038/s41598-018-37403-y
   PubMed Web of Science ®Google Scholar
• Barrow F, Khan S, Fredrickson G, et al. Microbiota-driven activation of Intrahepatic B cells aggravates NASH through innate and adaptive signaling. Hepatology. 2021;74(2):704–722. doi:10.1002/hep.31755
   PubMed Web of Science ®Google Scholar
• Zhang F, Jiang WW, Li X, et al. Role of intrahepatic B cells in non-alcoholic fatty liver disease by secreting pro-inflammatory cytokines and regulating intrahepatic T cells. J Dig Dis. 2016;17(7):464–474. doi:10.1111/1751-2980.12362
   PubMed Web of Science ®Google Scholar
• Bruzzì S, Sutti S, Giudici G, et al. B2-Lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD). Free Radic Biol Med. 2018;124:249–259. doi:10.1016/j.freeradbiomed.2018.06.015
   PubMed Web of Science ®Google Scholar
• Maleki I, Aminafshari MR, Taghvaei T, et al. Serum immunoglobulin A concentration is a reliable biomarker for liver fibrosis in non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20(35):12566–12573. doi:10.3748/wjg.v20.i35.12566
   PubMed Web of Science ®Google Scholar
• McPherson S, Henderson E, Burt AD, Day CP, Anstee QM. Serum immunoglobulin levels predict fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol. 2014;60(5):1055–1062. doi:10.1016/j.jhep.2014.01.010
   PubMed Web of Science ®Google Scholar
• Zhong Z, Nan K, Weng M, et al. Pro- and anti- effects of immunoglobulin A- producing B cell in tumors and its triggers. Front Immunol. 2021;12:765044. doi:10.3389/fimmu.2021.765044
   PubMed Web of Science ®Google Scholar
• Shalapour S, Lin XJ, Bastian IN, et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature. 2017;551(7680):340–345. doi:10.1038/nature24302
   PubMed Web of Science ®Google Scholar
• Hwang S, Yun H, Moon S, Cho YE, Gao B. Role of neutrophils in the pathogenesis of nonalcoholic steatohepatitis. Front Endocrinol (Lausanne). 2021;12:751802. doi:10.3389/fendo.2021.751802
   PubMed Web of Science ®Google Scholar
• Chen S, Guo H, Xie M, Zhou C, Zheng M. Neutrophil: an emerging player in the occurrence and progression of metabolic associated fatty liver disease. Int Immunopharmacol. 2021;97:107609. doi:10.1016/j.intimp.2021.107609
   PubMed Web of Science ®Google Scholar
• Chen J, Liang B, Bian D, et al. Knockout of neutrophil elastase protects against western diet induced nonalcoholic steatohepatitis in mice by regulating hepatic ceramides metabolism. Biochem Biophys Res Commun. 2019;518(4):691–697. doi:10.1016/j.bbrc.2019.08.111
   PubMed Web of Science ®Google Scholar
• Ou R, Liu J, Lv M, et al. Neutrophil depletion improves diet-induced non-alcoholic fatty liver disease in mice. Endocrine. 2017;57(1):72–82. doi:10.1007/s12020-017-1323-4
   PubMed Web of Science ®Google Scholar
• Zang S, Wang L, Ma X, et al. Neutrophils play a crucial role in the early stage of nonalcoholic steatohepatitis via neutrophil elastase in mice. Cell Biochem Biophys. 2015;73(2):479–487. doi:10.1007/s12013-015-0682-9
   PubMed Web of Science ®Google Scholar
• Ibusuki R, Uto H, Arima S, et al. Transgenic expression of human neutrophil peptide-1 enhances hepatic fibrosis in mice fed a choline-deficient, L-amino acid-defined diet. Liver Int. 2013;33(10):1549–1556. doi:10.1111/liv.12203
   PubMed Web of Science ®Google Scholar
• van der Windt DJ, Sud V, Zhang H, et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology. 2018;68(4):1347–1360. doi:10.1002/hep.29914
   PubMed Web of Science ®Google Scholar
• Hilscher MB, Shah VH. Neutrophil extracellular traps and liver disease. Semin Liver Dis. 2020;40(2):171–179. doi:10.1055/s-0039-3399562
   PubMed Web of Science ®Google Scholar
• Kanwal F, Kramer JR, Mapakshi S, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology. 2018;155(6):1828–1837.e2. doi:10.1053/j.gastro.2018.08.024
   PubMed Web of Science ®Google Scholar
• Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–444. doi:10.1038/nature07205
   PubMed Web of Science ®Google Scholar
• Peiseler M, Tacke F. Inflammatory mechanisms underlying nonalcoholic steatohepatitis and the transition to hepatocellular carcinoma. Cancers. 2021;13(4):730. doi:10.3390/cancers13040730
   PubMed Web of Science ®Google Scholar
• Dongiovanni P, Meroni M, Longo M, Fargion S, Fracanzani AL. Genetics, immunity and nutrition boost the switching from NASH to HCC. Biomedicines. 2021;9(11):1524. doi:10.3390/biomedicines9111524
   PubMed Web of Science ®Google Scholar
• Ibrahim SH, Hirsova P, Malhi H, Gores GJ. Animal models of nonalcoholic steatohepatitis: eat, delete, and inflame. Dig Dis Sci. 2016;61(5):1325–1336. doi:10.1007/s10620-015-3977-1
   PubMed Web of Science ®Google Scholar
• Carreres L, Jílková ZM, Vial G, et al. Modeling diet-induced NAFLD and NASH in rats: a comprehensive review. Biomedicines. 2021;9(4):378. doi:10.3390/biomedicines9040378
   PubMed Web of Science ®Google Scholar
• Asgharpour A, Cazanave SC, Pacana T, et al. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J Hepatol. 2016;65(3):579–588. doi:10.1016/j.jhep.2016.05.005
   PubMed Web of Science ®Google Scholar
• Geh D, Manas DM, Reeves HL. Hepatocellular carcinoma in non-alcoholic fatty liver disease-A review of an emerging challenge facing clinicians. Hepatobiliary Surg Nutr. 2021;10(1):59–75. doi:10.21037/hbsn.2019.08.08
   PubMed Web of Science ®Google Scholar
• Foerster F, Gairing SJ, Müller L, Galle PR. NAFLD-driven HCC: safety and efficacy of current and emerging treatment options. J Hepatol. 2022;76(2):446–457. doi:10.1016/j.jhep.2021.09.007
   PubMed Web of Science ®Google Scholar
• Lange NF, Radu P, Dufour JF. Prevention of NAFLD-associated HCC: role of lifestyle and chemoprevention. J Hepatol. 2021;75(5):1217–1227. doi:10.1016/j.jhep.2021.07.025
   PubMed Web of Science ®Google Scholar
• Simon TG, Henson J, Osganian S, et al. Daily aspirin use associated with reduced risk for fibrosis progression in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2019;17(13):2776–2784.e4. doi:10.1016/j.cgh.2019.04.061
   PubMed Web of Science ®Google Scholar
• Simon TG, Ma Y, Ludvigsson JF, et al. Association between aspirin use and risk of hepatocellular carcinoma. JAMA Oncol. 2018;4(12):1683–1690. doi:10.1001/jamaoncol.2018.4154
   PubMed Web of Science ®Google Scholar
• Zhang Y, Wang H, Xiao H. Metformin actions on the liver: protection mechanisms emerging in hepatocytes and immune cells against NASH-related HCC. Int J Mol Sci. 2021;22(9):5016. doi:10.3390/ijms22095016
   PubMed Web of Science ®Google Scholar
• Li S, Ghoshal S, Sojoodi M, et al. Pioglitazone reduces hepatocellular carcinoma development in two rodent models of cirrhosis. J Gastrointest Surg. 2019;23(1):101–111. doi:10.1007/s11605-018-4004-6
   PubMed Web of Science ®Google Scholar
• Ahsan F, Oliveri F, Goud HK, et al. Pleiotropic effects of statins in the light of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cureus. 2020;12(9):e10446. doi:10.7759/cureus.10446
   PubMed Web of Science ®Google Scholar
• Valkhoff VE, Sturkenboom MC, Kuipers EJ. Risk factors for gastrointestinal bleeding associated with low-dose aspirin. Best Pract Res Clin Gastroenterol. 2012;26(2):125–140. doi:10.1016/j.bpg.2012.01.011
   PubMed Web of Science ®Google Scholar
• Filipova E, Uzunova K, Kalinov K, Vekov T. Pioglitazone and the risk of bladder cancer: a meta-analysis. Diabetes Ther. 2017;8(4):705–726. doi:10.1007/s13300-017-0273-4
   PubMed Web of Science ®Google Scholar
• Kothari S, Dhami-Shah H, Shah SR. Antidiabetic drugs and statins in nonalcoholic fatty liver disease. J Clin Exp Hepatol. 2019;9(6):723–730. doi:10.1016/j.jceh.2019.06.003
   PubMed Web of Science ®Google Scholar
• Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–357. doi:10.1002/hep.29367
   PubMed Web of Science ®Google Scholar
• European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–1402. doi:10.1016/j.jhep.2015.11.004.
   PubMed Web of Science ®Google Scholar
• Raza S, Rajak S, Upadhyay A, Tewari A, Anthony Sinha R. Current treatment paradigms and emerging therapies for NAFLD/NASH. Front Biosci. 2021;26(2):206–237. doi:10.2741/4892
   Web of Science ®Google Scholar
• Pinto Lde F, Compri CM, Fornari JV, et al. The immunosuppressant drug, thalidomide, improves hepatic alterations induced by a high-fat diet in mice. Liver Int. 2010;30(4):603–610. doi:10.1111/j.1478-3231.2009.02200.x
   PubMed Web of Science ®Google Scholar
• Li Z, Yang S, Lin H, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology. 2003;37(2):343–350. doi:10.1053/jhep.2003.50048
   PubMed Web of Science ®Google Scholar
• Luangmonkong T, Suriguga S, Bigaeva E, et al. Evaluating the antifibrotic potency of galunisertib in a human ex vivo model of liver fibrosis. Br J Pharmacol. 2017;174(18):3107–3117. doi:10.1111/bph.13945
   PubMed Web of Science ®Google Scholar
• Lefebvre E, Moyle G, Reshef R, et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One. 2016;11(6):e0158156. doi:10.1371/journal.pone.0158156
   PubMed Web of Science ®Google Scholar
• Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label Phase 2 trial. Lancet Oncol. 2018;19(7):940–952. doi:10.1016/S1470-2045(18)30351-6
   PubMed Web of Science ®Google Scholar
• El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, Phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–2502. doi:10.1016/S0140-6736(17)31046-2
   PubMed Web of Science ®Google Scholar
• Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–1905. doi:10.1056/NEJMoa1915745
   PubMed Web of Science ®Google Scholar
• Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592(7854):450–456. doi:10.1038/s41586-021-03362-0
   PubMed Web of Science ®Google Scholar
• Dufour JF, Caussy C, Loomba R. Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges. Gut. 2020;69(10):1877–1884. doi:10.1136/gutjnl-2019-319104
   PubMed Web of Science ®Google Scholar