Beyond the liver: targeting the hepatic microenvironment and multi-organ networks for innovative MASH therapy

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) represents a progressive liver disease of a rapidly increasing global prevalence, driven by intricate pathophysiological interactions within the hepatic microenvironment and systemic crosstalk between the liver and peripheral organs. This review delineates the dynamic roles of key hepatic effector cells, including hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, in disease initiation and progression, highlighting how their dysregulated intercellular communication through soluble mediators and extracellular vesicles perpetuates a vicious cycle of lipotoxicity, inflammation, and fibrosis. Furthermore, we expound on the critical involvement of extrahepatic organ networks, specifically the gut-liver, adipose-liver, and muscle-liver axes, in exacerbating hepatic metabolic dysregulation via microbial dysbiosis, aberrant adipokine secretion, and myokine imbalances. The repeated failure of highly selective, single-target therapies in clinical trials underscores the multifactorial nature of MASH pathogenesis and necessitates a paradigm shift in therapeutic strategies. We propose that future innovations should embrace two novel perspectives: first, the development of multi-target agents capable of simultaneously rectifying aberrant multicellular crosstalk within the hepatic microenvironment; and second, the modulation of dynamic interplay between the liver and other organs to restore systemic metabolic homeostasis. Ultimately, integrating such multi-target approaches with precision medicine tailored to individual genetic and phenotypic profiles holds the key to curbing the growing MASH epidemic.

Keywords

MASH / hepatic microenvironment / fibrosis / inter-organ crosstalk / multi-target therapy / precision medicine

References

[1] Younossi Z,Marietti M.Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat Rev Gastroenterol Hepatol2018;15:11-20

[2] Rinella ME.Nonalcoholic fatty liver disease: a systematic review.JAMA2015;313:2263-73

[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.Lancet2024;403:1027-50 PMCID:PMC7615769

[4] Neeland IJ,Tchernof A.Metabolic syndrome.Nat Rev Dis Primers2024;10:77

[5] Younossi ZM,Abdelatif D,Henry L.Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology2016;64:73-84

[6] Mitra S,Chowdhury A.Epidemiology of non-alcoholic and alcoholic fatty liver diseases.Transl Gastroenterol Hepatol2020;5:16 PMCID:PMC7063528

[7] Estes C,Arias-Loste MT.Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.J Hepatol2018;69:896-904

[8] Asrani SK,Eaton J.Burden of liver diseases in the world.J Hepatol2019;70:151-71

[9] Charlton MR,Pedersen RA,Heimbach JK.Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.Gastroenterology2011;141:1249-53

[10] Estes C,Loomba R,Sanyal AJ.Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.Hepatology2018;67:123-33 PMCID:PMC5767767

[11] Younossi Z,Arrese M.Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.Hepatology2019;69:2672-82

[12] Targher G,Tilg H.MASLD: a systemic metabolic disorder with cardiovascular and malignant complications.Gut2024;73:691-702

[13] Huang DQ,Rinella ME.Metabolic dysfunction-associated steatotic liver disease in adults.Nat Rev Dis Primers2025;11:14

[14] Mittal S,Sada YH.Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol2016;14:124-31.e1 PMCID:PMC4690789

[15] Hardy T,Anstee QM.Nonalcoholic fatty liver disease: pathogenesis and disease spectrum.Annu Rev Pathol2016;11:451-96

[16] Bertot LC.Trends in hepatocellular carcinoma due to non-alcoholic fatty liver disease.Expert Rev Gastroenterol Hepatol2019;13:179-87

[17] Tilg H.Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.Hepatology2010;52:1836-46

[18] Connor CL.Fatty infiltration of the liver and the development of cirrhosis in diabetes and chronic alcoholism.Am J Pathol1938;14:347-64.9 PMCID:PMC1964950

[19] Chen Z,She Z,Li H.Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease.Free Radic Biol Med2020;152:116-41

[20] Schwärzler J,Grander C,Tilg H.The pathophysiology of MASLD: an immunometabolic perspective.Expert Rev Clin Immunol2024;20:375-86

[21] Friedman SL,Rinella M.Mechanisms of NAFLD development and therapeutic strategies.Nat Med2018;24:908-22 PMCID:PMC6553468

[22] Stefan N.Clusters of metabolic dysfunction-associated steatotic liver disease for precision medicine.Nat Rev Gastroenterol Hepatol2025;22:226-7

[23] Luukkonen PK,Ahlholm N.The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans.Cell Metab2023;35:1887-1896.e5

[24] Liu DJ,Yu H.Charge Diabetes Working GroupEPIC-InterAct ConsortiumEPIC-CVD ConsortiumGOLD ConsortiumVA Million Veteran ProgramExome-wide association study of plasma lipids in > 300,000 individuals.Nat Genet2017;49:1758-66 PMCID:PMC5709146

[25] Wu Q,Lin S,Yan Y.The microenvironment in the development of MASLD-MASH-HCC and associated therapeutic in MASH-HCC.Front Immunol2025;16:1569915 PMCID:PMC12074932

[26] Trefts E,Wasserman DH.The liver.Curr Biol2017;27:R1147-51 PMCID:PMC5897118

[27] Povero D,Ren W.Characterization and proteome of circulating extracellular vesicles as potential biomarkers for NASH.Hepatol Commun2020;4:1263-78 PMCID:PMC7471415

[28] Newman LA,Johnson J,Hopkins AM.Selective isolation of liver-derived extracellular vesicles redefines performance of miRNA biomarkers for non-alcoholic fatty liver disease.Biomedicines2022;10:195 PMCID:PMC8773667

[29] Xu Y,Hu S.Hepatocyte nuclear factor 4α prevents the steatosis-to-NASH progression by regulating p53 and bile acid signaling (in mice).Hepatology2021;73:2251-65 PMCID:PMC8062586

[30] Lan T,Hu F.Hepatocyte glutathione S-transferase mu 2 prevents non-alcoholic steatohepatitis by suppressing ASK1 signaling.J Hepatol2022;76:407-19

[31] An P,Zhao S.Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis.Nat Commun2020;11:2362 PMCID:PMC7217909

[32] Xiao Y,Hu W.Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis.Sci Transl Med2023;15:eadc9653 PMCID:PMC10234568

[33] Xu F,Huang W.Annexin A5 regulates hepatic macrophage polarization via directly targeting PKM2 and ameliorates NASH.Redox Biol2020;36:101634 PMCID:PMC7369618

[34] Liu XL,Cao HX.Lipotoxic hepatocyte-derived exosomal microRNA 192-5p activates macrophages through Rictor/Akt/Forkhead box transcription factor O1 signaling in nonalcoholic fatty liver disease.Hepatology2020;72:454-69 PMCID:PMC10465073

[35] Liao CY,Gao Y,Revzin A.Hepatocyte-derived lipotoxic extracellular vesicle sphingosine 1-phosphate induces macrophage chemotaxis.Front Immunol2018;9:2980 PMCID:PMC6305739

[36] Guo Q,Lucien F.Integrin β₁-enriched extracellular vesicles mediate monocyte adhesion and promote liver inflammation in murine NASH.J Hepatol2019;71:1193-205 PMCID:PMC6864271

[37] Dasgupta D,Mauer AS.IRE1A stimulates hepatocyte-derived extracellular vesicles that promote inflammation in mice with steatohepatitis.Gastroenterology2020;159:1487-1503.e17 PMCID:PMC7666601

[38] Hirsova P,Krishnan A.Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes.Gastroenterology2016;150:956-67 PMCID:PMC4808464

[39] Kumar S,Wu R,Su Q.Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis.Adv Drug Deliv Rev2021;176:113869 PMCID:PMC11792083

[40] Ma F,Hu Z.Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression.Hepatology2023;78:1492-505

[41] Chiabotto G,Tapparo M,Bruno S.Human liver stem cell-derived extracellular vesicles target hepatic stellate cells and attenuate their pro-fibrotic phenotype.Front Cell Dev Biol2021;9:777462 PMCID:PMC8593217

[42] Koenen MT,Kaczor DM.Extracellular vesicles from steatotic hepatocytes provoke pro-fibrotic responses in cultured stellate cells.Biomolecules2022;12:698 PMCID:PMC9138794

[43] Bruno S,Herrera Sanchez MB.HLSC-derived extracellular vesicles attenuate liver fibrosis and inflammation in a murine model of non-alcoholic steatohepatitis.Mol Ther2020;28:479-89 PMCID:PMC7001005

[44] Povero D,Eguchi A.Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ.Cell Mol Gastroenterol Hepatol2015;1:646-663.e4 PMCID:PMC4714359

[45] Liu X,Liu H.Hepatocyte-derived MASP1-enriched small extracellular vesicles activate HSCs to promote liver fibrosis.Hepatology2023;77:1181-97

[46] Baboota RK,Bonnet L.BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH.Nat Metab2022;4:1007-21 PMCID:PMC9398907

[47] Du K,Wang L.Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction.Nat Commun2025;16:3038 PMCID:PMC11953480

[48] Park J,Kim J.CO-induced TTP activation alleviates cellular senescence and age-dependent hepatic steatosis via downregulation of PAI-1.Aging Dis2023;14:484-501 PMCID:PMC10017156

[49] Antwi MB,Clarisse D.PPARα-ERRα crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression.Metabolism2025;164:156128

[50] Cooreman MP,Francque SM.MASLD/MASH and type 2 diabetes: two sides of the same coin?.Diabetes Res Clin Pract2024;212:111688

[51] Calle RA,Carvajal-Gonzalez S.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 Med2021;27:1836-48

[52] Chen L,Wei H.Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors.Expert Opin Investig Drugs2019;28:917-30

[53] Alkhouri N,Noureddin M,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 Drugs2020;29:135-41 PMCID:PMC7063378

[54] Loomba R,Kowdley KV.for the ATLAS InvestigatorsCombination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH.Hepatology2021;73:625-43

[55] Harrison SA,Guy CD.MAESTRO-NASH InvestigatorsA phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis.N Engl J Med2024;390:497-509

[56] Noureddin M,Harrison SA.Expert panel recommendations: practical clinical applications for initiating and monitoring resmetirom in patients with MASH/NASH and moderate to noncirrhotic advanced fibrosis.Clin Gastroenterol Hepatol2024;22:2367-77

[57] Harrison SA,Jabbar A.A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.J Hepatol2020;72:816-27

[58] Xie P,Pei WJ.Saponins derived from Gynostemma pentaphyllum regulate triglyceride and cholesterol metabolism and the mechanisms: a review.J Ethnopharmacol2024;319:117186

[59] Sandireddy R,Gupta P,Tripathi M.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 Biol2024;12:1433857 PMCID:PMC11289778

[60] Banales JM,Karlsen T,LaRusso NF.Cholangiocyte pathobiology.Nat Rev Gastroenterol Hepatol2019;16:269-81 PMCID:PMC6563606

[61] Galanakis V,Munteanu A.Transcriptomic and epigenetic mechanisms controlling cholangiocytes transdifferentiation into hepatocytes.J Hepatol2025:S0168-8278(25)02516

[62] Geier A,Grote T.Characterization of organic anion transporter regulation, glutathione metabolism and bile formation in the obese Zucker rat.J Hepatol2005;43:1021-30

[63] Jiao N,Chapa-Rodriguez A.Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.Gut2018;67:1881-91

[64] Coombes JD,Swiderska-Syn M.Osteopontin promotes cholangiocyte secretion of chemokines to support macrophage recruitment and fibrosis in MASH.Liver Int2025;45:e16131

[65] Ghallab A,Stirnimann G.Enteronephrohepatic circulation of bile acids and therapeutic potential of systemic bile acid transporter inhibitors.J Hepatol2025;83:1204-17

[66] Caballero-Camino FJ,Wångsell F.A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans.Hepatology2023;78:709-26 PMCID:PMC10442107

[67] Miethke AG,Porta G.Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Gastroenterol Hepatol2024;9:620-31

[68] Thompson RJ,Artan R.Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial.Lancet Gastroenterol Hepatol2022;7:830-42

[69] Dutta RK,Du K.Hedgehog signaling: implications in liver pathophysiology.Semin Liver Dis2023;43:418-28

[70] Xie G,Swiderska-Syn M.Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice.Hepatology2013;58:1801-13 PMCID:PMC3758784

[71] Dutta R,Peng Y,Grem JL.Pharmacokinetics and biodistribution of GDC-0449 loaded micelles in normal and liver fibrotic mice.Pharm Res2017;34:564-78

[72] Masters JC,Salageanu 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 Dev2021;10:707-17 PMCID:PMC8359308

[73] Roos FJM,Wu H.Human branching cholangiocyte organoids recapitulate functional bile duct formation.Cell Stem Cell2022;29:776-794.e13

[74] Wang XK.Targeting liver sinusoidal endothelial cells: an attractive therapeutic strategy to control inflammation in nonalcoholic fatty liver disease.Front Pharmacol2021;12:655557 PMCID:PMC8082362

[75] Yang Z,Xie K,Gan C.MASLD development: from molecular pathogenesis toward therapeutic strategies.Chin Med J2025;138:1807-24 PMCID:PMC12321477

[76] He Q,Dong H.Role of liver sinusoidal endothelial cell in metabolic dysfunction-associated fatty liver disease.Cell Commun Signal2024;22:346 PMCID:PMC11214243

[77] Maslak E,Chlopicki S.Liver sinusoidal endothelial cells (LSECs) function and NAFLD; NO-based therapy targeted to the liver.Pharmacol Rep2015;67:689-94

[78] Carambia A,Bruns OT.Inhibition of inflammatory CD4 T cell activity by murine liver sinusoidal endothelial cells.J Hepatol2013;58:112-8

[79] Nasiri-Ansari N,Flessa CM.Endothelial cell dysfunction and nonalcoholic fatty liver disease (NAFLD): a concise review.Cells2022;11:2511 PMCID:PMC9407007

[80] Furuta K,Pavelko KD.Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis.J Clin Invest2021;131:143690 PMCID:PMC7954604

[81] He S,Ma W.Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis.J Hepatol2024;81:135-48

[82] Bravo M,Barberá A.Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH.Dis Model Mech2021;14:dmm048884 PMCID:PMC8188885

[83] Luangmonkong T,Bigaeva E.Evaluating the antifibrotic potency of galunisertib in a human ex vivo model of liver fibrosis.Br J Pharmacol2017;174:3107-17 PMCID:PMC5573419

[84] Gao YX,Tang L,Luo SZ.Mertk⁺ liver sinusoidal endothelial cells negatively regulate PINK1 related mitophagy and accelerate MASH.Immun Inflamm Dis2025;13:e70256 PMCID:PMC12444409

[85] Jiang J,Wang J.Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism.Cell Metab2025;37:1119-1136.e13

[86] Wen Y,Ju C.Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities.Cell Mol Immunol2021;18:45-56 PMCID:PMC7852525

[87] Parthasarathy G.Macrophage heterogeneity in NASH: more than just nomenclature.Hepatology2021;74:515-8 PMCID:PMC8662756

[88] Takimoto Y,Nakamoto N.Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis.iScience2023;26:106220 PMCID:PMC9982274

[89] Lefere S.Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk with metabolism.JHEP Rep2019;1:30-43 PMCID:PMC7052781

[90] Van Herck MA,Kwanten WJ.The differential roles of T cells in non-alcoholic fatty liver disease and obesity.Front Immunol2019;10:82 PMCID:PMC6372559

[91] Gadd VL,Powell EE.The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease.Hepatology2014;59:1393-405

[92] Tacke F.Macrophage heterogeneity in liver injury and fibrosis.J Hepatol2014;60:1090-6

[93] Tran S,Poupel L.Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis.Immunity2020;53:627-640.e5

[94] Zhang J,Fan M.Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH.Cell Metab2024;36:1745-1763.e6

[95] Li Y,Sottas C.The mitochondrial TSPO ligand Atriol mitigates metabolic-associated steatohepatitis by downregulating CXCL1.Metabolism2024;159:155942 PMCID:PMC11374472

[96] Wan J,Teixeira-Clerc F.M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease.Hepatology2014;59:130-42

[97] Lee JL,Hsu YA.Galectin-12 modulates Kupffer cell polarization to alter the progression of nonalcoholic fatty liver disease.Glycobiology2023;33:673-82

[98] Jaitin DA,Thaiss CA.Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner.Cell2019;178:686-698.e14 PMCID:PMC7068689

[99] Daemen S,Kalugotla G.Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH.Cell Rep2021;34:108626 PMCID:PMC7877246

[100] Blacher E,Litichevskiy L.Aging disrupts circadian gene regulation and function in macrophages.Nat Immunol2022;23:229-36 PMCID:PMC9704320

[101] Qiu T,Wu J,Hu W.Mechanisms of rifaximin inhibition of hepatic fibrosis in mice with metabolic dysfunction associated steatohepatitis through the TLR4/NFκB pathway.Sci Rep2025;15:9815 PMCID:PMC11928543

[102] Saha P,Roy S.Peroxynitrite is key to Cylindrospermopsin-mediated MASLD to MASH progression via triggering TXNIP binding to NLRP3 and subsequent inflammasome activation.Toxicol Appl Pharmacol2025;504:117527

[103] Madan U,Awasthi A.Cenicriviroc, a CCR2/CCR5 antagonist, promotes the generation of type 1 regulatory T cells.Eur J Immunol2024;54:e2350847

[104] Anstee QM,Wai-Sun Wong V.Cenicriviroc lacked efficacy to treat liver fibrosis in nonalcoholic steatohepatitis: AURORA phase III randomized study.Clin Gastroenterol Hepatol2024;22:124-134.e1

[105] Higashi T,Hoshida Y.Hepatic stellate cells as key target in liver fibrosis.Adv Drug Deliv Rev2017;121:27-42 PMCID:PMC5682243

[106] Kamm DR.Hepatic stellate cells in physiology and pathology.J Physiol2022;600:1825-37 PMCID:PMC9012702

[107] Akkız H,Canbay A.Liver fibrosis: from basic science towards clinical progress, focusing on the central role of hepatic stellate cells.Int J Mol Sci2024;25:7873 PMCID:PMC11277292

[108] Tsuchida T.Mechanisms of hepatic stellate cell activation.Nat Rev Gastroenterol Hepatol2017;14:397-411

[109] Sanyal AJ,Ratziu V.The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.Hepatology2019;70:1913-27

[110] Mederacke I,Troeger JS.Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology.Nat Commun2013;4:2823 PMCID:PMC4059406

[111] Yang F,Li Y.Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis.Int Immunopharmacol2021;99:108051

[112] Schwabe RF,Pajvani UB.Mechanisms of fibrosis development in nonalcoholic steatohepatitis.Gastroenterology2020;158:1913-28 PMCID:PMC7682538

[113] Li S,Yu S.Hepatic stellate cell-released CXCL1 aggravates HCC malignant behaviors through the MIR4435-2HG/miR-506-3p/TGFB1 axis.Cancer Sci2023;114:504-20 PMCID:PMC9899617

[114] Kocabayoglu P,Lee YA.β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis.J Hepatol2015;63:141-7 PMCID:PMC4475471

[115] Serna-salas SA,Wu Z,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,Hong H,Khambu B.Hepatic senescence, the good and the bad.World J Gastroenterol2019;25:5069-81 PMCID:PMC6747293

[117] Coppé JP,Krtolica A.The senescence-associated secretory phenotype: the dark side of tumor suppression.Annu Rev Pathol2010;5:99-118 PMCID:PMC4166495

[118] Cheng N,Lau LF.Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2.JCI Insight2022;7:e158207 PMCID:PMC9431681

[119] Yashaswini CN,Bhattacharya D.Phenotypes and ontogeny of senescent hepatic stellate cells in metabolic dysfunction-associated steatohepatitis.J Hepatol2024;81:207-17 PMCID:PMC11269047

[120] Hu D,Zhong J.Cellular senescence and hematological malignancies: From pathogenesis to therapeutics.Pharmacol Ther2021;223:107817

[121] Wang S,Pickholz E.An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis.Sci Transl Med2023;15:eadd3949 PMCID:PMC10686705

[122] Dickson I.No anti-fibrotic effect of selonsertib in NASH.Nat Rev Gastroenterol Hepatol2020;17:260

[123] Harrison SA,Okanoue T.STELLAR-3STELLAR-4 InvestigatorsSelonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.J Hepatol2020;73:26-39

[124] Xu X,Wu L.Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH).Signal Transduct Target Ther2022;7:287 PMCID:PMC9376100

[125] Harrison SA,Caldwell S.GS-US-321-0105 and GS-US-321-0106 InvestigatorsSimtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis.Gastroenterology2018;155:1140-53

[126] Alkhouri N,Kabler H.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 Hepatol2022;77:607-18

[127] Harrison SA,Dubourg J,Alkhouri N.Challenges and opportunities in NASH drug development.Nat Med2023;29:562-73

[128] Ha S,Zhang X.Interplay between gut microbiome, host genetic and epigenetic modifications in MASLD and MASLD-related hepatocellular carcinoma.Gut2024;74:141-52 PMCID:PMC11671994

[129] Low ZS,Cheng HS.The LIDPAD mouse model captures the multisystem interactions and extrahepatic complications in MASLD.Adv Sci2024;11:e2404326 PMCID:PMC11425234

[130] Nie Q,Wang K.Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway.Cell2024;187:2717-2734.e33

[131] Wen YQ,Zhao GG.FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis.Acta Pharmacol Sin2024;45:2313-27 PMCID:PMC11489735

[132] Chen R,Gao J.3-O-acylated bile acids: disrupters or harmonizers of metabolism?.Trends Mol Med2025;31:103-5

[133] Zhou S,Wang P.A symbiotic filamentous gut fungus ameliorates MASH via a secondary metabolite-CerS6-ceramide axis.Science2025;388:eadp5540

[134] Wei W,Jia Z.Parabacteroides distasonis uses dietary inulin to suppress NASH via its metabolite pentadecanoic acid.Nat Microbiol2023;8:1534-48 PMCID:PMC10390331

[135] Aron-Wisnewsky J,Witjes J.Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders.Nat Rev Gastroenterol Hepatol2020;17:279-97

[136] Zhou Y,Yin P,Li H.Bacterial extracellular vesicles: emerging mediators of gut-liver axis crosstalk in hepatic diseases.Front Cell Infect Microbiol2025;15:1620829 PMCID:PMC12226546

[137] Grimaldi R,Vulevic J,Costabile A.Fermentation properties and potential prebiotic activity of Bimuno^® galacto-oligosaccharide (65% galacto-oligosaccharide content) on in vitro gut microbiota parameters.Br J Nutr2016;116:480-6 PMCID:PMC4937186

[138] Younossi ZM,Loomba R.REGENERATE Study InvestigatorsObeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.Lancet2019;394:2184-96

[139] Harrison SA,Lucas KJ.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 Hepatol2025;23:103-13

[140] Noureddin M,Lawitz EJ.TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial.Nat Med2025;31:2297-305 PMCID:PMC12283411

[141] Trauner M,Shiffman ML.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 Hepatol2019;4:445-53

[142] Wang K,Wang G,Wang H.FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid.Med Res Rev2024;44:568-86

[143] Chu Y,Chen X.Fibroblast growth factor receptor signaling in metabolic dysfunction-associated fatty liver disease: pathogenesis and therapeutic targets.Pharmacol Ther2025;269:108844

[144] Khalil SM,de Oliveira FD,Meine GC.Efficacy and safety of aldafermin for the treatment of metabolic dysfunction-associated steatohepatitis: a systematic review and meta-analysis.Clin Res Hepatol Gastroenterol2025;49:102579

[145] Noureddin M,Chalasani NP.Efruxifermin in compensated liver cirrhosis caused by MASH.N Engl J Med2025;392:2413-24

[146] Coste SC,Cozma A.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.Life2024;14:1327 PMCID:PMC11509161

[147] Nelson JE,Wilson LA.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 Gastroenterol2016;111:852-63 PMCID:PMC5361650

[148] Ratziu V,Safadi R.ARREST investigator study groupAramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.Nat Med2021;27:1825-35 PMCID:PMC12165723

[149] Ratziu V,Lazas D.Aramchol improves hepatic fibrosis in metabolic dysfunction-associated steatohepatitis: results of multimodality assessment using both conventional and digital pathology.Hepatology2025;81:932-46 PMCID:PMC12186543

[150] Hu S,Zhu Y.Loss of adipose ATF3 promotes adipose tissue lipolysis and the development of MASH.Commun Biol2024;7:1300 PMCID:PMC11467330

[151] Castañé H,Hernández-Aguilera A.Multi-omics profiling reveals altered mitochondrial metabolism in adipose tissue from patients with metabolic dysfunction-associated steatohepatitis.EBioMedicine2025;111:105532 PMCID:PMC11743550

[152] Pezzino S,Castorina M,Latteri S.Role of perturbated hemostasis in MASLD and its correlation with adipokines.Life2024;14:93 PMCID:PMC10820028

[153] Zhao K,Ding W.Adipokines regulate the development and progression of MASLD through organellar oxidative stress.Hepatol Commun2025;9:e0639 PMCID:PMC11781772

[154] Wu KK,Wu M.MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice.Nat Commun2024;15:8624 PMCID:PMC11452520

[155] Hutchison AL,Romeo S.Endocrine aspects of metabolic dysfunction-associated steatotic liver disease (MASLD): Beyond insulin resistance.J Hepatol2023;79:1524-41

[156] Stefan N,Birkenfeld AL,White MF.The role of hepatokines in NAFLD.Cell Metab2023;35:236-52 PMCID:PMC10157895

[157] Pal D,Kundu R.Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance.Nat Med2012;18:1279-85

[158] Georgiadi A,Merahbi RE.Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue.Nat Commun2021;12:2999 PMCID:PMC8137956

[159] Wu C,Gao R.Elevated circulating follistatin associates with an increased risk of type 2 diabetes.Nat Commun2021;12:6486 PMCID:PMC8580990

[160] Nabi O,Boursier J.Lean individuals with NAFLD have more severe liver disease and poorer clinical outcomes (NASH-CO Study).Hepatology2023;78:272-83

[161] Chun HS.Lean vs. obese phenotypes of nonalcoholic fatty liver disease: similar or different?.Clin Mol Hepatol2023;29:377-80 PMCID:PMC10121299

[162] Gofton C,George J.Lean metabolic-associated fatty liver disease.Endocrinol Metab Clin North Am2023;52:431-44

[163] Chen H,Wan J.PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets.Pharmacol Ther2023;245:108391

[164] Francque SM,Ratziu V.NATIVE Study GroupA randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.N Engl J Med2021;385:1547-58

[165] Gawrieh S,Loo N.Saroglitazar, a PPAR-α/γ agonist, for treatment of NAFLD: a randomized controlled double-blind phase 2 trial.Hepatology2021;74:1809-24

[166] Hakeem AN,Tawfiq RA.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 Pharmacother2023;157:114050

[167] Armstrong MJ,Guo K.Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.J Hepatol2016;64:399-408 PMCID:PMC4713865

[168] Loomba R,Lawitz EJ.Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis.N Engl J Med2024;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 Rep2025;44:115732

[170] Ipsen DH.Extracellular vesicles as drivers of non-alcoholic fatty liver disease: small particles with big impact.Biomedicines2021;9:93 PMCID:PMC7832840

[171] Cheng L,Li F.Human umbilical cord-derived mesenchymal stem cell-exosomal miR-627-5p ameliorates non-alcoholic fatty liver disease by repressing FTO expression.Hum Cell2021;34:1697-708

[172] Zhao Y,Jiang S.Liver governs adipose remodelling via extracellular vesicles in response to lipid overload.Nat Commun2020;11:719 PMCID:PMC7002740

[173] Zhou Q,Wu G.Adipose progenitor cell-derived extracellular vesicles suppress macrophage M1 program to alleviate midlife obesity.Nat Commun2025;16:2743 PMCID:PMC11926339

[174] Tang Y,Liu H.Exosomal miR-27b-3p secreted by visceral adipocytes contributes to endothelial inflammation and atherogenesis.Cell Rep2023;42:111948

[175] Tamimi A,Sedighi-Pirsaraei N.Exosome prospects in the diagnosis and treatment of non-alcoholic fatty liver disease.Front Med2024;11:1420281 PMCID:PMC11322140

[176] Marjot T,Stine JG.Skeletal muscle and MASLD: mechanistic and clinical insights.Hepatol Commun2025;9:e0711 PMCID:PMC12106243

[177] Kumbaroğlu BF,Düger T.Mudscle strength and cardiovascular health in MASLD: a prospective study.Medicina2025;61:247 PMCID:PMC11857117

[178] Lanthier N.Does the benefit of optimal MASH treatment depend on a reduction in myosteatosis?.Clin Res Hepatol Gastroenterol2025;49:102640

[179] Schwarz JM,Dare D.Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets.Am J Clin Nutr2003;77:43-50

[180] Brown MS.Selective versus total insulin resistance: a pathogenic paradox.Cell Metab2008;7:95-6

[181] Bourie A, Potier JB, Pinget M, Bouzakri K. Myokines: crosstalk and consequences on liver physiopathology.Nutrients2023;15:1729 PMCID:PMC10096786

[182] Perakakis N,Fernández-Real JM.Physiology and role of irisin in glucose homeostasis.Nat Rev Endocrinol2017;13:324-37 PMCID:PMC5878942

[183] Guo M,Li J.Irisin ameliorates age-associated sarcopenia and metabolic dysfunction.J Cachexia Sarcopenia Muscle2023;14:391-405 PMCID:PMC9891925

[184] Wang Y,Bian H.Apelin promotes hepatic fibrosis through ERK signaling in LX-2 cells.Mol Cell Biochem2019;460:205-15 PMCID:PMC6745032

[185] Izumiya Y,Ouchi N,Kharitonenkov A.FGF21 is an Akt-regulated myokine.FEBS Lett2008;582:3805-10 PMCID:PMC2604129

[186] Gong Q,Zhang F.Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice.Hepatology2016;64:425-38 PMCID:PMC5726522

[187] Newsome PN.Therapeutic horizons in metabolic dysfunction-associated steatohepatitis.J Clin Invest2025;135:e186425 PMCID:PMC12208534

[188] Booth L,Roberts JL.The SCD1 inhibitor aramchol interacts with regorafenib to kill GI tumor cells in vitro and in vivo.Oncotarget2025;16:662-78 PMCID:PMC12581408