REFERENCES
1. Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11-20.
3. Risk Factor Collaboration (NCD-RisC). Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3,663 population-representative studies with 222 million children, adolescents, and adults. Lancet. 2024;403:1027-50.
5. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73-84.
6. Mitra S, De A, Chowdhury A. Epidemiology of non-alcoholic and alcoholic fatty liver diseases. Transl Gastroenterol Hepatol. 2020;5:16.
7. Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol. 2018;69:896-904.
8. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019;70:151-71.
9. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141:1249-53.
10. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67:123-33.
11. Younossi Z, Tacke F, Arrese M, et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2019;69:2672-82.
12. Targher G, Byrne CD, Tilg H. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut. 2024;73:691-702.
13. Huang DQ, Wong VWS, Rinella ME, et al. Metabolic dysfunction-associated steatotic liver disease in adults. Nat Rev Dis Primers. 2025;11:14.
14. 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;14:124-31.e1.
15. Hardy T, Oakley F, Anstee QM, Day CP. Nonalcoholic fatty liver disease: pathogenesis and disease spectrum. Annu Rev Pathol. 2016;11:451-96.
16. Bertot LC, Adams LA. Trends in hepatocellular carcinoma due to non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol. 2019;13:179-87.
17. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836-46.
18. Connor CL. Fatty infiltration of the liver and the development of cirrhosis in diabetes and chronic alcoholism. Am J Pathol. 1938;14:347-64.9.
19. Chen Z, Tian R, She Z, Cai J, Li H. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease. Free Radic Biol Med. 2020;152:116-41.
20. Schwärzler J, Grabherr F, Grander C, Adolph TE, Tilg H. The pathophysiology of MASLD: an immunometabolic perspective. Expert Rev Clin Immunol. 2024;20:375-86.
21. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908-22.
22. Stefan N, Targher G. Clusters of metabolic dysfunction-associated steatotic liver disease for precision medicine. Nat Rev Gastroenterol Hepatol. 2025;22:226-7.
23. Luukkonen PK, Porthan K, Ahlholm N, et al. The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. Cell Metab. 2023;35:1887-1896.e5.
24. Liu DJ, Peloso GM, Yu H, et al.; Charge Diabetes Working Group. Exome-wide association study of plasma lipids in > 300,000 individuals. Nat Genet. 2017;49:1758-66.
25. Wu Q, Yang Y, Lin S, Geller DA, Yan Y. The microenvironment in the development of MASLD-MASH-HCC and associated therapeutic in MASH-HCC. Front Immunol. 2025;16:1569915.
27. Povero D, Yamashita H, Ren W, et al. Characterization and proteome of circulating extracellular vesicles as potential biomarkers for NASH. Hepatol Commun. 2020;4:1263-78.
28. Newman LA, Useckaite Z, Johnson J, Sorich MJ, Hopkins AM, Rowland A. Selective isolation of liver-derived extracellular vesicles redefines performance of miRNA biomarkers for non-alcoholic fatty liver disease. Biomedicines. 2022;10:195.
29. Xu Y, Zhu Y, Hu S, et al. Hepatocyte nuclear factor 4α prevents the steatosis-to-NASH progression by regulating p53 and bile acid signaling (in mice). Hepatology. 2021;73:2251-65.
30. Lan T, Hu Y, Hu F, et al. Hepatocyte glutathione S-transferase mu 2 prevents non-alcoholic steatohepatitis by suppressing ASK1 signaling. J Hepatol. 2022;76:407-19.
31. An P, Wei LL, Zhao S, et al. Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis. Nat Commun. 2020;11:2362.
32. Xiao Y, Batmanov K, Hu W, et al. Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Sci Transl Med. 2023;15:eadc9653.
33. Xu F, Guo M, Huang W, et al. Annexin A5 regulates hepatic macrophage polarization via directly targeting PKM2 and ameliorates NASH. Redox Biol. 2020;36:101634.
34. Liu XL, Pan Q, Cao HX, et al. Lipotoxic hepatocyte-derived exosomal microRNA 192-5p activates macrophages through Rictor/Akt/Forkhead box transcription factor O1 signaling in nonalcoholic fatty liver disease. Hepatology. 2020;72:454-69.
35. Liao CY, Song MJ, Gao Y, Mauer AS, Revzin A, Malhi H. Hepatocyte-derived lipotoxic extracellular vesicle sphingosine 1-phosphate induces macrophage chemotaxis. Front Immunol. 2018;9:2980.
36. Guo Q, Furuta K, Lucien F, et al. Integrin β1-enriched extracellular vesicles mediate monocyte adhesion and promote liver inflammation in murine NASH. J Hepatol. 2019;71:1193-205.
37. Dasgupta D, Nakao Y, Mauer AS, et al. IRE1A stimulates hepatocyte-derived extracellular vesicles that promote inflammation in mice with steatohepatitis. Gastroenterology. 2020;159:1487-1503.e17.
38. Hirsova P, Ibrahim SH, Krishnan A, et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology. 2016;150:956-67.
39. Kumar S, Duan Q, Wu R, Harris EN, Su Q. Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis. Adv Drug Deliv Rev. 2021;176:113869.
40. Ma F, Liu Y, Hu Z, et al. Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression. Hepatology. 2023;78:1492-505.
41. Chiabotto G, Ceccotti E, Tapparo M, Camussi G, Bruno S. Human liver stem cell-derived extracellular vesicles target hepatic stellate cells and attenuate their pro-fibrotic phenotype. Front Cell Dev Biol. 2021;9:777462.
42. Koenen MT, Brandt EF, Kaczor DM, et al. Extracellular vesicles from steatotic hepatocytes provoke pro-fibrotic responses in cultured stellate cells. Biomolecules. 2022;12:698.
43. Bruno S, Pasquino C, Herrera Sanchez MB, et al. HLSC-derived extracellular vesicles attenuate liver fibrosis and inflammation in a murine model of non-alcoholic steatohepatitis. Mol Ther. 2020;28:479-89.
44. Povero D, Panera N, Eguchi A, et al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ. Cell Mol Gastroenterol Hepatol. 2015;1:646-663.e4.
45. Liu X, Tan S, Liu H, et al. Hepatocyte-derived MASP1-enriched small extracellular vesicles activate HSCs to promote liver fibrosis. Hepatology. 2023;77:1181-97.
46. Baboota RK, Rawshani A, Bonnet L, et al. BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH. Nat Metab. 2022;4:1007-21.
47. Du K, Umbaugh DS, Wang L, et al. Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction. Nat Commun. 2025;16:3038.
48. Park J, Chen Y, Kim J, et al. CO-induced TTP activation alleviates cellular senescence and age-dependent hepatic steatosis via downregulation of PAI-1. Aging Dis. 2023;14:484-501.
49. Antwi MB, Lefere S, Clarisse D, et al. PPARα-ERRα crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression. Metabolism. 2025;164:156128.
50. Cooreman MP, Vonghia L, Francque SM. MASLD/MASH and type 2 diabetes: two sides of the same coin? Diabetes Res Clin Pract. 2024;212:111688.
51. Calle RA, Amin NB, Carvajal-Gonzalez S, et al. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials. Nat Med. 2021;27:1836-48.
52. Chen L, Duan Y, Wei H, et al. Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors. Expert Opin Investig Drugs. 2019;28:917-30.
53. Alkhouri N, Lawitz E, Noureddin M, DeFronzo R, Shulman GI. GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020;29:135-41.
54. Loomba R, Noureddin M, Kowdley KV, et al.; for the ATLAS Investigators. Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH. Hepatology. 2021;73:625-43.
55. Harrison SA, Bedossa P, Guy CD, et al.; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497-509.
56. Noureddin M, Charlton MR, Harrison SA, et al. Expert panel recommendations: practical clinical applications for initiating and monitoring resmetirom in patients with MASH/NASH and moderate to noncirrhotic advanced fibrosis. Clin Gastroenterol Hepatol. 2024;22:2367-77.
57. Harrison SA, Goodman Z, Jabbar A, et al. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J Hepatol. 2020;72:816-27.
58. Xie P, Luo HT, Pei WJ, et al. Saponins derived from Gynostemma pentaphyllum regulate triglyceride and cholesterol metabolism and the mechanisms: a review. J Ethnopharmacol. 2024;319:117186.
59. Sandireddy R, Sakthivel S, Gupta P, Behari J, Tripathi M, Singh BK. Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases. Front Cell Dev Biol. 2024;12:1433857.
60. Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol. 2019;16:269-81.
61. Galanakis V, Gribben C, Munteanu A, et al. Transcriptomic and epigenetic mechanisms controlling cholangiocytes transdifferentiation into hepatocytes. J Hepatol. ;2025:S0168-8278(25)02516.
62. Geier A, Dietrich CG, Grote T, et al. Characterization of organic anion transporter regulation, glutathione metabolism and bile formation in the obese Zucker rat. J Hepatol. 2005;43:1021-30.
63. Jiao N, Baker SS, Chapa-Rodriguez A, et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut. 2018;67:1881-91.
64. Coombes JD, Manka PP, Swiderska-Syn M, et al. Osteopontin promotes cholangiocyte secretion of chemokines to support macrophage recruitment and fibrosis in MASH. Liver Int. 2025;45:e16131.
65. Ghallab A, Mandorfer M, Stirnimann G, et al. Enteronephrohepatic circulation of bile acids and therapeutic potential of systemic bile acid transporter inhibitors. J Hepatol. 2025;83:1204-17.
66. Caballero-Camino FJ, Rodrigues PM, Wångsell F, et al. A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans. Hepatology. 2023;78:709-26.
67. Miethke AG, Moukarzel A, Porta G, et al. Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2024;9:620-31.
68. Thompson RJ, Arnell H, Artan R, et al. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2022;7:830-42.
69. Dutta RK, Jun J, Du K, Diehl AM. Hedgehog signaling: implications in liver pathophysiology. Semin Liver Dis. 2023;43:418-28.
70. Xie G, Karaca G, Swiderska-Syn M, et al. Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice. Hepatology. 2013;58:1801-13.
71. Dutta R, Kumar V, Peng Y, Evande RE, Grem JL, Mahato RI. Pharmacokinetics and biodistribution of GDC-0449 loaded micelles in normal and liver fibrotic mice. Pharm Res. 2017;34:564-78.
72. Masters JC, LaBadie RR, Salageanu J, Li J, Shaik N. Pharmacokinetics and safety of glasdegib in participants with moderate/severe hepatic impairment: a phase I, single-dose, matched case-control study. Clin Pharmacol Drug Dev. 2021;10:707-17.
73. Roos FJM, van Tienderen GS, Wu H, et al. Human branching cholangiocyte organoids recapitulate functional bile duct formation. Cell Stem Cell. 2022;29:776-794.e13.
74. Wang XK, Peng ZG. Targeting liver sinusoidal endothelial cells: an attractive therapeutic strategy to control inflammation in nonalcoholic fatty liver disease. Front Pharmacol. 2021;12:655557.
75. Yang Z, Zhao J, Xie K, Tang C, Gan C, Gao J. MASLD development: from molecular pathogenesis toward therapeutic strategies. Chin Med J. 2025;138:1807-24.
76. He Q, He W, Dong H, et al. Role of liver sinusoidal endothelial cell in metabolic dysfunction-associated fatty liver disease. Cell Commun Signal. 2024;22:346.
77. Maslak E, Gregorius A, Chlopicki S. Liver sinusoidal endothelial cells (LSECs) function and NAFLD; NO-based therapy targeted to the liver. Pharmacol Rep. 2015;67:689-94.
78. Carambia A, Frenzel C, Bruns OT, et al. Inhibition of inflammatory CD4 T cell activity by murine liver sinusoidal endothelial cells. J Hepatol. 2013;58:112-8.
79. Nasiri-Ansari N, Androutsakos T, Flessa CM, et al. Endothelial cell dysfunction and nonalcoholic fatty liver disease (NAFLD): a concise review. Cells. 2022;11:2511.
80. Furuta K, Guo Q, Pavelko KD, et al. Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis. J Clin Invest. 2021;131:143690.
81. He S, Luo Y, Ma W, et al. Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis. J Hepatol. 2024;81:135-48.
82. Bravo M, Raurell I, Barberá A, et al. Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH. Dis Model Mech. 2021;14:dmm048884.
83. 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;174:3107-17.
84. Gao YX, Weng Z, Tang L, Xu MY, Luo SZ. Mertk+ liver sinusoidal endothelial cells negatively regulate PINK1 related mitophagy and accelerate MASH. Immun Inflamm Dis. 2025;13:e70256.
85. Jiang J, Gao Y, Wang J, et al. Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism. Cell Metab. 2025;37:1119-1136.e13.
86. Wen Y, Lambrecht J, Ju C, Tacke F. Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities. Cell Mol Immunol. 2021;18:45-56.
87. Parthasarathy G, Malhi H. Macrophage heterogeneity in NASH: more than just nomenclature. Hepatology. 2021;74:515-8.
88. Takimoto Y, Chu PS, Nakamoto N, et al. Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis. iScience. 2023;26:106220.
89. Lefere S, Tacke F. Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk with metabolism. JHEP Rep. 2019;1:30-43.
90. 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.
91. Gadd VL, Skoien R, Powell EE, et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology. 2014;59:1393-405.
92. Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol. 2014;60:1090-6.
93. Tran S, Baba I, Poupel L, et al. Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis. Immunity. 2020;53:627-640.e5.
94. Zhang J, Wang Y, Fan M, et al. Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH. Cell Metab. 2024;36:1745-1763.e6.
95. Li Y, Chen L, Sottas C, et al. The mitochondrial TSPO ligand Atriol mitigates metabolic-associated steatohepatitis by downregulating CXCL1. Metabolism. 2024;159:155942.
96. 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;59:130-42.
97. Lee JL, Wang YC, Hsu YA, et al. Galectin-12 modulates Kupffer cell polarization to alter the progression of nonalcoholic fatty liver disease. Glycobiology. 2023;33:673-82.
98. Jaitin DA, Adlung L, Thaiss CA, et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell. 2019;178:686-698.e14.
99. Daemen S, Gainullina A, Kalugotla G, et al. Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH. Cell Rep. 2021;34:108626.
100. Blacher E, Tsai C, Litichevskiy L, et al. Aging disrupts circadian gene regulation and function in macrophages. Nat Immunol. 2022;23:229-36.
101. Qiu T, Zhu X, Wu J, Hong W, Hu W, Fang T. Mechanisms of rifaximin inhibition of hepatic fibrosis in mice with metabolic dysfunction associated steatohepatitis through the TLR4/NFκB pathway. Sci Rep. 2025;15:9815.
102. Saha P, Bose D, Roy S, et al. Peroxynitrite is key to Cylindrospermopsin-mediated MASLD to MASH progression via triggering TXNIP binding to NLRP3 and subsequent inflammasome activation. Toxicol Appl Pharmacol. 2025;504:117527.
103. Madan U, Verma B, Awasthi A. Cenicriviroc, a CCR2/CCR5 antagonist, promotes the generation of type 1 regulatory T cells. Eur J Immunol. 2024;54:e2350847.
104. Anstee QM, Neuschwander-Tetri BA, Wai-Sun Wong V, et al. Cenicriviroc lacked efficacy to treat liver fibrosis in nonalcoholic steatohepatitis: AURORA phase III randomized study. Clin Gastroenterol Hepatol. 2024;22:124-134.e1.
105. Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev. 2017;121:27-42.
106. Kamm DR, McCommis KS. Hepatic stellate cells in physiology and pathology. J Physiol. 2022;600:1825-37.
107. Akkız H, Gieseler RK, Canbay A. Liver fibrosis: from basic science towards clinical progress, focusing on the central role of hepatic stellate cells. Int J Mol Sci. 2024;25:7873.
108. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14:397-411.
109. Sanyal AJ, Harrison SA, Ratziu V, et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials. Hepatology. 2019;70:1913-27.
110. Mederacke I, Hsu CC, Troeger JS, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun. 2013;4:2823.
111. Yang F, Li H, Li Y, et al. Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis. Int Immunopharmacol. 2021;99:108051.
112. Schwabe RF, Tabas I, Pajvani UB. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology. 2020;158:1913-28.
113. Li S, Hu X, Yu S, et al. Hepatic stellate cell-released CXCL1 aggravates HCC malignant behaviors through the MIR4435-2HG/miR-506-3p/TGFB1 axis. Cancer Sci. 2023;114:504-20.
114. Kocabayoglu P, Lade A, Lee YA, et al. β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J Hepatol. 2015;63:141-7.
115. Serna-salas SA, Soto-gámez AA, Wu Z, Klaver M, Moshage H. Studying hepatic stellate cell senescence. In: Weiskirchen R, Friedman SL, Editors. Hepatic Stellate Cells. New York: Springer US; 2023. pp. 79-109.
116. Huda N, Liu G, Hong H, Yan S, Khambu B, Yin XM. Hepatic senescence, the good and the bad. World J Gastroenterol. 2019;25:5069-81.
117. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118.
118. Cheng N, Kim KH, Lau LF. Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2. JCI Insight. 2022;7:e158207.
119. Yashaswini CN, Qin T, Bhattacharya D, et al. Phenotypes and ontogeny of senescent hepatic stellate cells in metabolic dysfunction-associated steatohepatitis. J Hepatol. 2024;81:207-17.
120. Hu D, Yuan S, Zhong J, et al. Cellular senescence and hematological malignancies: From pathogenesis to therapeutics. Pharmacol Ther. 2021;223:107817.
121. Wang S, Li K, Pickholz E, et al. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2023;15:eadd3949.
122. Dickson I. No anti-fibrotic effect of selonsertib in NASH. Nat Rev Gastroenterol Hepatol. 2020;17:260.
123. Harrison SA, Wong VW, Okanoue T, et al.; STELLAR-3. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials. J Hepatol. 2020;73:26-39.
124. Xu X, Poulsen KL, Wu L, et al. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther. 2022;7:287.
125. Harrison SA, Abdelmalek MF, Caldwell S, et al.; GS-US-321-0105 and GS-US-321-0106 Investigators. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology. 2018;155:1140-53.
126. Alkhouri N, Herring R, Kabler H, et al. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. J Hepatol. 2022;77:607-18.
127. Harrison SA, Allen AM, Dubourg J, Noureddin M, Alkhouri N. Challenges and opportunities in NASH drug development. Nat Med. 2023;29:562-73.
128. Ha S, Wong VW, Zhang X, Yu J. Interplay between gut microbiome, host genetic and epigenetic modifications in MASLD and MASLD-related hepatocellular carcinoma. Gut. 2024;74:141-52.
129. Low ZS, Chua D, Cheng HS, et al. The LIDPAD mouse model captures the multisystem interactions and extrahepatic complications in MASLD. Adv Sci. 2024;11:e2404326.
130. Nie Q, Luo X, Wang K, et al. Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway. Cell. 2024;187:2717-2734.e33.
131. Wen YQ, Zou ZY, Zhao GG, et al. FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis. Acta Pharmacol Sin. 2024;45:2313-27.
132. Chen R, Chen X, Gao J. 3-O-acylated bile acids: disrupters or harmonizers of metabolism? Trends Mol Med. 2025;31:103-5.
133. Zhou S, Li M, Wang P, et al. A symbiotic filamentous gut fungus ameliorates MASH via a secondary metabolite-CerS6-ceramide axis. Science. 2025;388:eadp5540.
134. Wei W, Wong CC, Jia Z, et al. Parabacteroides distasonis uses dietary inulin to suppress NASH via its metabolite pentadecanoic acid. Nat Microbiol. 2023;8:1534-48.
135. Aron-Wisnewsky J, Vigliotti C, Witjes J, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol. 2020;17:279-97.
136. Zhou Y, Sun Y, Yin P, Zuo S, Li H, Cao K. Bacterial extracellular vesicles: emerging mediators of gut-liver axis crosstalk in hepatic diseases. Front Cell Infect Microbiol. 2025;15:1620829.
137. Grimaldi R, Swann JR, Vulevic J, Gibson GR, Costabile A. Fermentation properties and potential prebiotic activity of Bimuno® galacto-oligosaccharide (65% galacto-oligosaccharide content) on in vitro gut microbiota parameters. Br J Nutr. 2016;116:480-6.
138. Younossi ZM, Ratziu V, Loomba R, et al.; REGENERATE Study Investigators. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394:2184-96.
139. Harrison SA, Frias JP, Lucas KJ, et al. Safety and efficacy of efruxifermin in combination with a GLP-1 receptor agonist in patients with NASH/MASH and type 2 diabetes in a randomized phase 2 study. Clin Gastroenterol Hepatol. 2025;23:103-13.
140. Noureddin M, Alkhouri N, Lawitz EJ, et al. TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial. Nat Med. 2025;31:2297-305.
141. Trauner M, Nevens F, Shiffman ML, et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study. Lancet Gastroenterol Hepatol. 2019;4:445-53.
142. Wang K, Zhang Y, Wang G, Hao H, Wang H. FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid. Med Res Rev. 2024;44:568-86.
143. Chu Y, Yang S, Chen X. Fibroblast growth factor receptor signaling in metabolic dysfunction-associated fatty liver disease: pathogenesis and therapeutic targets. Pharmacol Ther. 2025;269:108844.
144. Khalil SM, de Souza MHG, de Oliveira FD, Sato EDBS, Meine GC. Efficacy and safety of aldafermin for the treatment of metabolic dysfunction-associated steatohepatitis: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol. 2025;49:102579.
145. Noureddin M, Rinella ME, Chalasani NP, et al. Efruxifermin in compensated liver cirrhosis caused by MASH. N Engl J Med. 2025;392:2413-24.
146. Coste SC, Hilda Orășan O, Cozma A, et al. Allelic, genotypic, and haplotypic analysis of cytokine IL17A, IL17F, and toll-like receptor TLR4 gene polymorphisms in metabolic-dysfunction-associated steatotic liver disease: insights from an exploratory study. Life. 2024;14:1327.
147. Nelson JE, Roth CL, Wilson LA, et al. Vitamin D deficiency is associated with increased risk of non-alcoholic steatohepatitis in adults with non-alcoholic fatty liver disease: possible role for MAPK and NF-κB? Am J Gastroenterol. 2016;111:852-63.
148. Ratziu V, de Guevara L, Safadi R, et al.; ARREST investigator study group. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat Med. 2021;27:1825-35.
149. Ratziu V, Yilmaz Y, Lazas D, et al. Aramchol improves hepatic fibrosis in metabolic dysfunction-associated steatohepatitis: results of multimodality assessment using both conventional and digital pathology. Hepatology. 2025;81:932-46.
150. Hu S, Cassim Bawa FN, Zhu Y, et al. Loss of adipose ATF3 promotes adipose tissue lipolysis and the development of MASH. Commun Biol. 2024;7:1300.
151. Castañé H, Jiménez-Franco A, Hernández-Aguilera A, et al. Multi-omics profiling reveals altered mitochondrial metabolism in adipose tissue from patients with metabolic dysfunction-associated steatohepatitis. EBioMedicine. 2025;111:105532.
152. Pezzino S, Luca T, Castorina M, Puleo S, Latteri S, Castorina S. Role of perturbated hemostasis in MASLD and its correlation with adipokines. Life. 2024;14:93.
153. Zhao K, Zhang H, Ding W, et al. Adipokines regulate the development and progression of MASLD through organellar oxidative stress. Hepatol Commun. 2025;9:e0639.
154. Wu KK, Xu X, Wu M, et al. MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice. Nat Commun. 2024;15:8624.
155. Hutchison AL, Tavaglione F, Romeo S, Charlton M. Endocrine aspects of metabolic dysfunction-associated steatotic liver disease (MASLD): Beyond insulin resistance. J Hepatol. 2023;79:1524-41.
156. Stefan N, Schick F, Birkenfeld AL, Häring HU, White MF. The role of hepatokines in NAFLD. Cell Metab. 2023;35:236-52.
157. Pal D, Dasgupta S, Kundu R, et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med. 2012;18:1279-85.
158. Georgiadi A, Lopez-Salazar V, Merahbi RE, et al. Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue. Nat Commun. 2021;12:2999.
159. Wu C, Borné Y, Gao R, et al. Elevated circulating follistatin associates with an increased risk of type 2 diabetes. Nat Commun. 2021;12:6486.
160. Nabi O, Lapidus N, Boursier J, et al. Lean individuals with NAFLD have more severe liver disease and poorer clinical outcomes (NASH-CO Study). Hepatology. 2023;78:272-83.
161. Chun HS, Lee M. Lean vs. obese phenotypes of nonalcoholic fatty liver disease: similar or different? Clin Mol Hepatol. 2023;29:377-80.
162. Gofton C, Clark-Dickson M, George J. Lean metabolic-associated fatty liver disease. Endocrinol Metab Clin North Am. 2023;52:431-44.
163. Chen H, Tan H, Wan J, et al. PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets. Pharmacol Ther. 2023;245:108391.
164. Francque SM, Bedossa P, Ratziu V, et al.; NATIVE Study Group. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N Engl J Med. 2021;385:1547-58.
165. Gawrieh S, Noureddin M, Loo N, et al. Saroglitazar, a PPAR-α/γ agonist, for treatment of NAFLD: a randomized controlled double-blind phase 2 trial. Hepatology. 2021;74:1809-24.
166. Hakeem AN, Kamal MM, Tawfiq RA, et al. Elafibranor modulates ileal macrophage polarization to restore intestinal integrity in NASH: potential crosstalk between ileal IL-10/STAT3 and hepatic TLR4/NF-κB axes. Biomed Pharmacother. 2023;157:114050.
167. Armstrong MJ, Hull D, Guo K, et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016;64:399-408.
168. Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391:299-310.
169. Lay S, Scherer PE. Exploring adipose tissue-derived extracellular vesicles in inter-organ crosstalk: implications for metabolic regulation and adipose tissue function. Cell Rep. 2025;44:115732.
170. Ipsen DH, Tveden-Nyborg P. Extracellular vesicles as drivers of non-alcoholic fatty liver disease: small particles with big impact. Biomedicines. 2021;9:93.
171. Cheng L, Yu P, Li F, et al. Human umbilical cord-derived mesenchymal stem cell-exosomal miR-627-5p ameliorates non-alcoholic fatty liver disease by repressing FTO expression. Hum Cell. 2021;34:1697-708.
172. Zhao Y, Zhao MF, Jiang S, et al. Liver governs adipose remodelling via extracellular vesicles in response to lipid overload. Nat Commun. 2020;11:719.
173. Zhou Q, Gao J, Wu G, et al. Adipose progenitor cell-derived extracellular vesicles suppress macrophage M1 program to alleviate midlife obesity. Nat Commun. 2025;16:2743.
174. Tang Y, Yang LJ, Liu H, et al. Exosomal miR-27b-3p secreted by visceral adipocytes contributes to endothelial inflammation and atherogenesis. Cell Rep. 2023;42:111948.
175. Tamimi A, Javid M, Sedighi-Pirsaraei N, Mirdamadi A. Exosome prospects in the diagnosis and treatment of non-alcoholic fatty liver disease. Front Med. 2024;11:1420281.
176. Marjot T, Armstrong MJ, Stine JG. Skeletal muscle and MASLD: mechanistic and clinical insights. Hepatol Commun. 2025;9:e0711.
177. Kumbaroğlu BF, Balaban YH, Düger T. Mudscle strength and cardiovascular health in MASLD: a prospective study. Medicina. 2025;61:247.
178. Lanthier N. Does the benefit of optimal MASH treatment depend on a reduction in myosteatosis? Clin Res Hepatol Gastroenterol. 2025;49:102640.
179. Schwarz JM, Linfoot P, Dare D, Aghajanian K. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets. Am J Clin Nutr. 2003;77:43-50.
180. Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 2008;7:95-6.
181. Bourie A, Potier JB, Pinget M, Bouzakri K. Myokines: crosstalk and consequences on liver physiopathology. Nutrients. 2023;15:1729.
182. Perakakis N, Triantafyllou GA, Fernández-Real JM, et al. Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol. 2017;13:324-37.
183. Guo M, Yao J, Li J, et al. Irisin ameliorates age-associated sarcopenia and metabolic dysfunction. J Cachexia Sarcopenia Muscle. 2023;14:391-405.
184. Wang Y, Song J, Bian H, et al. Apelin promotes hepatic fibrosis through ERK signaling in LX-2 cells. Mol Cell Biochem. 2019;460:205-15.
185. Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt-regulated myokine. FEBS Lett. 2008;582:3805-10.
186. Gong Q, Hu Z, Zhang F, et al. Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice. Hepatology. 2016;64:425-38.
187. Newsome PN, Loomba R. Therapeutic horizons in metabolic dysfunction-associated steatohepatitis. J Clin Invest. 2025;135:e186425.
