{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:49:19Z","timestamp":1785905359366,"version":"3.56.0"},"reference-count":151,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["K12 HD105271"],"award-info":[{"award-number":["K12 HD105271"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["K12 HD105271"],"award-info":[{"award-number":["K12 HD105271"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"University of California San Diego Altman Clinical and Translational Research Institute (ACTRI)\/NIH","award":["KL2TR001444"],"award-info":[{"award-number":["KL2TR001444"]}]},{"name":"American Association for the Study of Liver Diseases Foundation","award":["#PNC22-159963"],"award-info":[{"award-number":["#PNC22-159963"]}]},{"award":["#PNC22-159963"],"award-info":[{"award-number":["#PNC22-159963"]}],"id":[{"id":"https:\/\/ror.org\/005tjs461","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020172","name":"San Diego Digestive Diseases Research Center","doi-asserted-by":"crossref","award":["P30 DK120515"],"award-info":[{"award-number":["P30 DK120515"]}],"id":[{"id":"10.13039\/100020172","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of liver injury ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), a progressive inflammatory state associated with hepatocyte injury, fibrosis, cirrhosis, and hepatocellular carcinoma. Increasing evidence suggests that progression to MASH is not spatially uniform across the liver. Instead, it reflects region-specific metabolic stress, inflammatory signaling, and fibrogenic remodeling along the porto-central axis of the hepatic lobule. Recent advances in spatial transcriptomics, lipidomics, proteomics, and multiplex imaging have provided new insight into how hepatocytes, immune cells, endothelial cells, and hepatic stellate cells interact within distinct hepatic microenvironments during disease progression. In this review, we discuss emerging concepts linking hepatic zonation to steatosis, inflammation, fibrosis, and extracellular matrix remodeling in MASLD and MASH. We highlight how disruption of normal lobular organization contributes to a progressive loss of metabolic compartmentalization and to the amplification of inflammatory and fibrogenic signaling. We additionally examine how spatial disease programs differ between adult and pediatric MASLD, particularly given the periportal-predominant injury patterns frequently observed in children and the current lack of pediatric-focused mechanistic studies. Finally, we discuss recently approved therapies and emerging therapeutic strategies within the context of hepatic microenvironment remodeling and disease heterogeneity. Collectively, these findings support a framework in which MASLD and MASH are spatially organized diseases driven by dynamic multicellular interactions, emphasizing the importance of incorporating zonation and tissue context into future mechanistic studies and therapeutic development.<\/jats:p>","DOI":"10.3390\/biom16081129","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T10:24:07Z","timestamp":1785752647000},"page":"1129","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MASLD: Spatial Mechanisms and New Therapeutics"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0682-8808","authenticated-orcid":false,"given":"Christian","family":"Stoess","sequence":"first","affiliation":[{"name":"Department of Surgery School of Medicine and Health, Technical University of Munich, TUM University Hospital, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3924-8487","authenticated-orcid":false,"given":"Janset","family":"Onyuru","sequence":"additional","affiliation":[{"name":"Department of Surgery School of Medicine and Health, Technical University of Munich, TUM University Hospital, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5580-2938","authenticated-orcid":false,"given":"Yanzhu","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Surgery School of Medicine and Health, Technical University of Munich, TUM University Hospital, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Surgery School of Medicine and Health, Technical University of Munich, TUM University Hospital, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyi","family":"Xin","sequence":"additional","affiliation":[{"name":"Department of Surgery School of Medicine and Health, Technical University of Munich, TUM University Hospital, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aryan","family":"Panchal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0984, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillipp","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0984, USA"},{"name":"Division of Gastroenterology, Hepatology & Nutrition, Rady Children\u2019s Hospital San Diego, San Diego, CA 92123, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): A systematic review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.3350\/cmh.2024.0431","article-title":"Epidemiology of metabolic dysfunction-associated steatotic liver disease","volume":"31","author":"Younossi","year":"2025","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/j.jhep.2025.06.020","article-title":"Prevalence, severity and determinants of steatotic liver disease among individuals with metabolic and alcohol risk from the community","volume":"83","author":"Hansen","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/S2213-8587(24)00318-8","article-title":"Metabolic dysfunction-associated steatotic liver disease: Heterogeneous pathomechanisms and effectiveness of metabolism-based treatment","volume":"13","author":"Stefan","year":"2025","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.jhep.2023.06.003","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"79","author":"Rinella","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1056\/NEJMoa2309000","article-title":"A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis","volume":"390","author":"Harrison","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1056\/NEJMoa2413258","article-title":"Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis","volume":"392","author":"Sanyal","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1542\/peds.2006-1212","article-title":"Prevalence of fatty liver in children and adolescents","volume":"118","author":"Schwimmer","year":"2006","journal-title":"Pediatrics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1097\/HEP.0000000000000383","article-title":"Global and national prevalence of nonalcoholic fatty liver disease in adolescents: An analysis of the global burden of disease study 2019","volume":"78","author":"Hartmann","year":"2023","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jpeds.2018.11.021","article-title":"Prevalence of Nonalcoholic Fatty Liver Disease in Children with Obesity","volume":"207","author":"Yu","year":"2019","journal-title":"J. Pediatr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1097\/HEP.0000000000001440","article-title":"Call to action-Pediatric MASLD requires immediate attention to curb health crisis","volume":"82","author":"Hartmann","year":"2025","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/cld.1027","article-title":"Epidemiology of Pediatric Nonalcoholic Fatty Liver Disease","volume":"17","author":"Yu","year":"2021","journal-title":"Clin. Liver Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00431-024-05848-1","article-title":"Pediatric MASLD: Current understanding and practical approach","volume":"184","author":"Stroes","year":"2024","journal-title":"Eur. J. Pediatr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e186422","DOI":"10.1172\/JCI186422","article-title":"MASLD in children: Integrating epidemiological trends with mechanistic and translational advances","volume":"135","author":"Schwimmer","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/jpn3.12402","article-title":"Pharmacological management of pediatric metabolic dysfunction-associated steatotic liver disease","volume":"80","author":"Hartmann","year":"2025","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"100058","DOI":"10.1016\/j.pharmr.2025.100058","article-title":"Antiobesity medications in adult and pediatric obesity and metabolic dysfunction-associated steatotic liver disease","volume":"77","author":"Rodriguez","year":"2025","journal-title":"Pharmacol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1053\/j.gastro.2015.04.043","article-title":"Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease","volume":"149","author":"Angulo","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1002\/hep.27368","article-title":"Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up","volume":"61","author":"Ekstedt","year":"2015","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1002\/hep.20842","article-title":"Histopathology of pediatric nonalcoholic fatty liver disease","volume":"42","author":"Schwimmer","year":"2005","journal-title":"Hepatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e186423","DOI":"10.1172\/JCI186423","article-title":"Metabolic dysfunction-associated steatotic liver disease and the gut microbiome: Pathogenic insights and therapeutic innovations","volume":"135","author":"Schnabl","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e16169","DOI":"10.1111\/liv.16169","article-title":"MASLD, At-Risk MASH and Increased Liver Stiffness Are Associated with Young Adulthood Obesity Without Residual Risk After Losing Obesity","volume":"45","author":"Pustjens","year":"2025","journal-title":"Liver Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.jhep.2024.04.031","article-title":"EASL\u2013EASD\u2013EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD)","volume":"81","author":"Tacke","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1152\/physrev.00013.2007","article-title":"Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver","volume":"88","author":"Friedman","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S2213-8587(18)30154-2","article-title":"Non-alcoholic fatty liver disease: Causes, diagnosis, cardiometabolic consequences, and treatment strategies","volume":"7","author":"Stefan","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/S2468-1253(20)30077-7","article-title":"Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: A systematic review and meta-analysis","volume":"5","author":"Ye","year":"2020","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"C1637","DOI":"10.1152\/ajpcell.00951.2024","article-title":"Pathophysiological underpinnings of metabolic dysfunction-associated steatotic liver disease","volume":"328","author":"Kuchay","year":"2025","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_31","first-page":"745","article-title":"Overview of Lean MASH and MASLD","volume":"20","author":"Wong","year":"2024","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.jhep.2016.08.019","article-title":"Sarcopenia is an independent risk factor for non-alcoholic steatohepatitis and significant fibrosis","volume":"66","author":"Koo","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ezeani, C., Omaliko, C., Protiva, P., Al-Ajlouni, Y.A., Ketwaroo, G., and Njei, B. (2025). Cancer disparities in lean vs. non-lean MASH: Insight from a national inpatient sample. BMC Gastroenterol., 25.","DOI":"10.1186\/s12876-025-04187-1"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e240115","DOI":"10.1530\/JOE-24-0115","article-title":"The role of adipose tissue dysfunction in hepatic insulin resistance and T2D","volume":"262","author":"Sancar","year":"2024","journal-title":"J. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.cmet.2024.04.006","article-title":"Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease","volume":"36","author":"Bo","year":"2024","journal-title":"Cell Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1136\/gutjnl-2024-332398","article-title":"Interplay between gut microbiome, host genetic and epigenetic modifications in MASLD and MASLD-related hepatocellular carcinoma","volume":"74","author":"Ha","year":"2024","journal-title":"Gut"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1002\/hep.25539","article-title":"Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease","volume":"55","author":"Lomonaco","year":"2012","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11595","DOI":"10.1038\/s41467-025-66296-5","article-title":"Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance","volume":"16","author":"Tao","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13293-024-00617-z","article-title":"Fatty Liver Index (FLI) is the best score to predict MASLD with 50% lower cut-off value in women than in men","volume":"15","author":"Crudele","year":"2024","journal-title":"Biol. Sex. Differ."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1172\/JCI134165","article-title":"Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease","volume":"130","author":"Smith","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41574-025-01199-5","article-title":"Interleukin-18 in obesity and obesity-related metabolic diseases","volume":"22","author":"Stoess","year":"2026","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1016\/j.jhep.2023.07.033","article-title":"Incretins (GLP-1 receptor agonists and dual\/triple agonists) and the liver","volume":"79","author":"Newsome","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e0484","DOI":"10.1097\/HC9.0000000000000484","article-title":"Gut microbial metabolites in MASLD: Implications of mitochondrial dysfunction in the pathogenesis and treatment","volume":"8","author":"Zhang","year":"2024","journal-title":"Hepatol. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Vallianou, N.G., Kounatidis, D., Psallida, S., Vythoulkas-Biotis, N., Adamou, A., Zachariadou, T., Kargioti, S., Karampela, I., and Dalamaga, M. (2024). NAFLD\/MASLD and the Gut-Liver Axis: From Pathogenesis to Treatment Options. Metabolites, 14.","DOI":"10.3390\/metabo14070366"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.jhep.2024.06.017","article-title":"Histological improvements following energy restriction and exercise: The role of insulin resistance in resolution of MASH","volume":"81","author":"Mucinski","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.jhep.2025.02.033","article-title":"Integrative metabolism in MASLD and MASH: Pathophysiology and emerging mechanisms","volume":"83","author":"Steinberg","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1097\/HEP.0000000000001475","article-title":"Chiglitazar in MASLD with hypertriglyceridemia and insulin resistance: A phase II, randomized, double-blind, placebo-controlled study","volume":"83","author":"Sun","year":"2026","journal-title":"Hepatology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1002\/hep.29676","article-title":"Modulation of the intestinal bile acid\/farnesoid X receptor\/fibroblast growth factor 15 axis improves alcoholic liver disease in mice","volume":"67","author":"Hartmann","year":"2018","journal-title":"Hepatology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2307568","DOI":"10.1080\/19490976.2024.2307568","article-title":"Gut microbiota-derived indole compounds attenuate metabolic dysfunction-associated steatotic liver disease by improving fat metabolism and inflammation","volume":"16","author":"Min","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"609","DOI":"10.4254\/wjh.v15.i5.609","article-title":"Noninvasive biomarkers in pediatric nonalcoholic fatty liver disease","volume":"15","author":"Jayasekera","year":"2023","journal-title":"World J. Hepatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/cld.685","article-title":"Risk factors for progression of and treatment options for NAFLD in children","volume":"11","author":"Hartmann","year":"2018","journal-title":"Clin. Liver Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1007\/s00018-018-2860-6","article-title":"Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease","volume":"75","author":"Ipsen","year":"2018","journal-title":"Cell Mol. Life Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1007\/s10620-016-4054-0","article-title":"Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease","volume":"61","author":"Softic","year":"2016","journal-title":"Dig. Dis. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.jhep.2018.01.019","article-title":"Fructose and sugar: A major mediator of non-alcoholic fatty liver disease","volume":"68","author":"Jensen","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1002\/hep.26226","article-title":"Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease","volume":"58","author":"Begriche","year":"2013","journal-title":"Hepatology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.jhep.2018.06.008","article-title":"Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease","volume":"69","author":"Lebeaupin","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Stoess, C., Leszczynska, A., Kui, L., and Feldstein, A.E. (2023). Pyroptosis and gasdermins-Emerging insights and therapeutic opportunities in metabolic dysfunction-associated steatohepatitis. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1218807"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Stoess, C., Choi, Y.K., Onyuru, J., Friess, H., Hoffman, H.M., Hartmann, D., and Feldstein, A.E. (2024). Cell Death in Liver Disease and Liver Surgery. Biomedicines, 12.","DOI":"10.3390\/biomedicines12030559"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1002\/hep.31518","article-title":"Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade","volume":"73","author":"Tilg","year":"2021","journal-title":"Hepatology"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Zazueta, A., Valenzuela-P\u00e9rez, L., Ortiz-L\u00f3pez, N., Pinto-Le\u00f3n, A., Torres, V., Gui\u00f1ez, D., Aliaga, N., Merino, P., Sandoval, A., and Covarrubias, N. (2024). Alteration of Gut Microbiota Composition in the Progression of Liver Damage in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084387"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"M\u00fcnte, E., and Hartmann, P. (2025). The Role of Short-Chain Fatty Acids in Metabolic Dysfunction-Associated Steatotic Liver Disease and Other Metabolic Diseases. Biomolecules, 15.","DOI":"10.3390\/biom15040469"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"M\u00fcnte, E., Viebahn, G., Khurana, A., Fujiki, J., Nakamura, T., Lang, S., Demir, M., Schnabl, B., and Hartmann, P. (2025). Faecalibacterium prausnitzii Is Associated with Disease Severity in MASLD but Its Supplementation Does Not Improve Diet-Induced Steatohepatitis in Mice. Microorganisms, 13.","DOI":"10.3390\/microorganisms13030675"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"G42","DOI":"10.1152\/ajpgi.00017.2023","article-title":"Probiotics, prebiotics, and synbiotics in nonalcoholic fatty liver disease and alcohol-associated liver disease","volume":"325","author":"Kaufmann","year":"2023","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/j.jhep.2021.11.029","article-title":"The fecal mycobiome in non-alcoholic fatty liver disease","volume":"76","author":"Demir","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.jhep.2022.12.006","article-title":"Fungal infections and the fungal microbiome in hepatobiliary disorders","volume":"78","author":"Hartmann","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2307586","DOI":"10.1080\/19490976.2024.2307586","article-title":"Fungal signature differentiates alcohol-associated liver disease from nonalcoholic fatty liver disease","volume":"16","author":"Viebahn","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1053\/j.gastro.2020.07.005","article-title":"Intestinal Virome Signature Associated With Severity of Nonalcoholic Fatty Liver Disease","volume":"159","author":"Lang","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Saha, P., and Hartmann, P. (2025). Impact of Gut Microbiome on Gut Permeability in Liver and Gut Diseases. Microorganisms, 13.","DOI":"10.3390\/microorganisms13061188"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2331460","DOI":"10.1080\/19490976.2024.2331460","article-title":"Breaking the barriers: The role of gut homeostasis in Metabolic-Associated Steatotic Liver Disease (MASLD)","volume":"16","author":"Cubero","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Rotaru, A., Stafie, R., Stratina, E., Zenovia, S., Nastasa, R., Minea, H., Huiban, L., Cuciureanu, T., Muzica, C., and Chiriac, S. (2025). Lean MASLD and IBD: Exploring the Intersection of Metabolic Dysfunction and the Gut-Liver Axis. Life, 15.","DOI":"10.3390\/life15020288"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2304157","DOI":"10.1080\/19490976.2024.2304157","article-title":"Disruption of gut barrier integrity and host-microbiome interactions underlie MASLD severity in patients with type-2 diabetes mellitus","volume":"16","author":"Forlano","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature10809","article-title":"Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity","volume":"482","author":"Elinav","year":"2012","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1055\/s-0040-1719174","article-title":"New Developments in Microbiome in Alcohol-Associated and Nonalcoholic Fatty Liver Disease","volume":"41","author":"Hartmann","year":"2021","journal-title":"Semin. Liver Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"G563","DOI":"10.1152\/ajpgi.00370.2018","article-title":"Gut microbiota in liver disease: Too much is harmful, nothing at all is not helpful either","volume":"316","author":"Hartmann","year":"2019","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/s41575-025-01068-6","article-title":"Hepatic stellate cells: Balancing homeostasis, hepatoprotection and fibrogenesis in health and disease","volume":"22","author":"Schwabe","year":"2025","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1038\/s41591-022-02016-6","article-title":"Microbiome-derived ethanol in nonalcoholic fatty liver disease","volume":"28","author":"Meijnikman","year":"2022","journal-title":"Nat. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41575-019-0134-x","article-title":"Spatial heterogeneity in the mammalian liver","volume":"16","author":"Itzkovitz","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1002\/hep.510300607","article-title":"Microanatomy of the human liver-exploring the hidden interfaces","volume":"30","author":"Saxena","year":"1999","journal-title":"Hepatology"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"\u00d6zkan, A., Stolley, D., Cressman, E.N.K., McMillin, M., DeMorrow, S., Yankeelov, T.E., and Rylander, M.N. (2020). The Influence of Chronic Liver Diseases on Hepatic Vasculature: A Liver-on-a-chip Review. Micromachines, 11.","DOI":"10.3390\/mi11050487"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.jhep.2018.01.005","article-title":"Development of the liver: Insights into organ and tissue morphogenesis","volume":"68","author":"Ober","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ajpath.2021.09.007","article-title":"Role and Regulation of Wnt\/\u03b2-Catenin in Hepatic Perivenous Zonation and Physiological Homeostasis","volume":"192","author":"Goel","year":"2022","journal-title":"Am. J. Pathol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4150","DOI":"10.1038\/s41467-018-06611-5","article-title":"Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control","volume":"9","author":"Brosch","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/nature21065","article-title":"Single-cell spatial reconstruction reveals global division of labour in the mammalian liver","volume":"542","author":"Halpern","year":"2017","journal-title":"Nature"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.mehy.2013.01.032","article-title":"Hedgehog signalling pathway in adult liver: A major new player in hepatocyte metabolism and zonation?","volume":"80","author":"Hovhannisyan","year":"2013","journal-title":"Med. Hypotheses"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1002\/hep.24156","article-title":"Hedgehog activity, epithelial-mesenchymal transitions, and biliary dysmorphogenesis in biliary atresia","volume":"53","author":"Omenetti","year":"2011","journal-title":"Hepatology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nrgastro.2013.183","article-title":"NAFLD, NASH and liver cancer","volume":"10","author":"Michelotti","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e0667","DOI":"10.1097\/HC9.0000000000000667","article-title":"Cellular communication networks in fibrosis: Insights from the MASLD pig model","volume":"9","author":"Zhang","year":"2025","journal-title":"Hepatol. Commun."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/s42255-020-00323-1","article-title":"Space-time logic of liver gene expression at sub-lobular scale","volume":"3","author":"Droin","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1038\/s42255-019-0109-9","article-title":"Spatial sorting enables comprehensive characterization of liver zonation","volume":"1","author":"Shapira","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1038\/s41586-026-10377-y","article-title":"A spatial atlas of the healthy human liver from live donors","volume":"653","author":"Yakubovsky","year":"2026","journal-title":"Nature"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"107322","DOI":"10.1016\/j.jbc.2024.107322","article-title":"Spatial transcriptomics unravels palmitoylation and zonation-dependent gene regulation by AEG-1 in mouse liver","volume":"300","author":"Saverino","year":"2024","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/s41586-019-1631-3","article-title":"Resolving the fibrotic niche of human liver cirrhosis at single-cell level","volume":"575","author":"Ramachandran","year":"2019","journal-title":"Nature"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"7046","DOI":"10.1038\/s41467-021-27354-w","article-title":"Spatial Transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver","volume":"12","author":"Hildebrandt","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/s42255-026-01459-2","article-title":"Single-cell spatial proteomics maps human liver zonation patterns and their vulnerability to disruption in tissue architecture","volume":"8","author":"Weiss","year":"2026","journal-title":"Nat. Metab."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.molcel.2019.07.028","article-title":"Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis","volume":"75","author":"Xiong","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1016\/j.celrep.2019.10.024","article-title":"Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis","volume":"29","author":"Dobie","year":"2019","journal-title":"Cell Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.jhep.2022.06.012","article-title":"Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease\u2014Novel insights into cellular communication circuits","volume":"77","author":"Peiseler","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.immuni.2020.08.004","article-title":"Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver","volume":"53","author":"Remmerie","year":"2020","journal-title":"Immunity"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/s41586-025-08677-w","article-title":"Hepatic stellate cells control liver zonation, size and functions via R-spondin 3","volume":"640","author":"Sugimoto","year":"2025","journal-title":"Nature"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"100599","DOI":"10.1016\/j.jlr.2024.100599","article-title":"Spatial lipidomics reveals zone-specific hepatic lipid alteration and remodeling in metabolic dysfunction-associated steatohepatitis","volume":"65","author":"Seubnooch","year":"2024","journal-title":"J. Lipid Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"eadn5228","DOI":"10.1126\/sciadv.adn5228","article-title":"Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis","volume":"10","author":"Khanal","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/s41467-024-55325-4","article-title":"Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution","volume":"16","author":"Watson","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1097\/HEP.0000000000000323","article-title":"AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease","volume":"77","author":"Rinella","year":"2023","journal-title":"Hepatology"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1136\/gutjnl-2023-331401","article-title":"MASH Resolution Index: Development and validation of a non-invasive score to detect histological resolution of MASH","volume":"73","author":"Loomba","year":"2024","journal-title":"Gut"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/jpn3.12420","article-title":"Dihydroxyacetone phosphate is a novel predictor of hepatic fibrosis in Latino adolescents with obesity","volume":"80","author":"Schenker","year":"2025","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/S2468-1253(23)00272-8","article-title":"Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): A multicentre, randomised, double-blind, placebo-controlled, phase 2b trial","volume":"8","author":"Harrison","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.cgh.2024.02.022","article-title":"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","volume":"23","author":"Harrison","year":"2025","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.jhep.2025.09.019","article-title":"Consensus position statements for the standardized application of histological grading and staging systems in MASH clinical trials","volume":"84","author":"Lackner","year":"2026","journal-title":"J. Hepatol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.jhep.2026.02.016","article-title":"Update in clinical science: MASLD in children and adolescents","volume":"84","author":"Lefere","year":"2026","journal-title":"J. Hepatol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"e186425","DOI":"10.1172\/JCI186425","article-title":"Therapeutic horizons in metabolic dysfunction-associated steatohepatitis","volume":"135","author":"Newsome","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1053\/j.gastro.2021.10.051","article-title":"Expert Panel Review to Compare FDA and EMA Guidance on Drug Development and Endpoints in Nonalcoholic Steatohepatitis","volume":"162","author":"Loomba","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"3128","DOI":"10.1038\/s41591-025-03799-0","article-title":"Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis","volume":"31","author":"Jara","year":"2025","journal-title":"Nat. Med."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"155835","DOI":"10.1016\/j.metabol.2024.155835","article-title":"Resmetirom, the first approved drug for the management of metabolic dysfunction-associated steatohepatitis: Trials, opportunities, and challenges","volume":"154","author":"Kokkorakis","year":"2024","journal-title":"Metabolism"},{"key":"ref_115","unstructured":"Madrigal Pharmaceuticals, Inc (2026, May 31). Madrigal Receives European Commission Approval for Rezdiffra\u2122 (resmetirom) for the Treatment of MASH with Moderate to Advanced Liver Fibrosis. Available online: https:\/\/ir.madrigalpharma.com\/news-releases\/news-release-details\/madrigal-receives-european-commission-approval-rezdiffratm."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.cgh.2023.04.003","article-title":"Cenicriviroc Lacked Efficacy to Treat Liver Fibrosis in Nonalcoholic Steatohepatitis: AURORA Phase III Randomized Study","volume":"22","author":"Anstee","year":"2024","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jhep.2020.02.027","article-title":"Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials","volume":"73","author":"Harrison","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1056\/NEJMoa2401943","article-title":"Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis","volume":"391","author":"Loomba","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa2401755","article-title":"A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis","volume":"391","author":"Sanyal","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1056\/NEJMoa2036205","article-title":"A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH","volume":"385","author":"Francque","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1056\/NEJMoa2304286","article-title":"Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH","volume":"389","author":"Loomba","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1056\/NEJMoa2502242","article-title":"Efruxifermin in Compensated Liver Cirrhosis Caused by MASH","volume":"392","author":"Noureddin","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/S2468-1253(24)00246-2","article-title":"Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: A multicentre, double-blind, randomised, placebo-controlled, phase 2b trial","volume":"9","author":"Loomba","year":"2024","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1016\/j.cell.2026.02.001","article-title":"Selective targeting of endothelial and perivascular angiocrine ROCK2 treats liver fibrosis","volume":"189","author":"Hu","year":"2026","journal-title":"Cell"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s44355-024-00004-w","article-title":"Resmetirom and GLP-1 agonists for MASH: Complementary rather than exclusive","volume":"1","author":"Zhou","year":"2024","journal-title":"npj Gut Liver"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.livres.2025.10.004","article-title":"Resmetirom and beyond: A new era in MASLD therapeutics","volume":"9","author":"Simmons","year":"2025","journal-title":"Liver Res."},{"key":"ref_127","unstructured":"U.S. Food and Drug Administration (2026, May 31). FDA Approves Treatment for Serious Liver Disease Known as \u2018MASH\u2019, Available online: https:\/\/www.fda.gov\/drugs\/news-events-human-drugs\/fda-approves-treatment-serious-liver-disease-known-mash."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/s41591-022-02200-8","article-title":"Tropifexor for nonalcoholic steatohepatitis: An adaptive, randomized, placebo-controlled phase 2a\/b trial","volume":"29","author":"Sanyal","year":"2023","journal-title":"Nat. Med."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.jhep.2024.04.034","article-title":"FGF21 agonists: An emerging therapeutic for metabolic dysfunction-associated steatohepatitis and beyond","volume":"81","author":"Harrison","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_130","unstructured":"ClinicalTrials.gov (2026, May 31). Research Study on Whether a Combination of 2 Medicines (NNC0194-0499 and Semaglutide) Works in People with Non-Alcoholic Steatohepatitis (NASH) (NCT05016882), Available online: https:\/\/clinicaltrials.gov\/study\/NCT05016882."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"e16186","DOI":"10.1111\/liv.16186","article-title":"Targeting PNPLA3 to Treat MASH and MASH Related Fibrosis and Cirrhosis","volume":"45","author":"Tesz","year":"2025","journal-title":"Liver Int."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jhep.2024.12.046","article-title":"AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: Two randomized phase I trials","volume":"83","author":"Armisen","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1056\/NEJMc2402341","article-title":"Phase 1 Trials of PNPLA3 siRNA in I148M Homozygous Patients with MAFLD","volume":"391","author":"Fabbrini","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.jhep.2025.05.031","article-title":"Phase I randomized double-blind study of an RNA interference therapeutic targeting HSD17B13 for metabolic dysfunction-associated steatohepatitis","volume":"83","author":"Sanyal","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nrgastro.2017.42","article-title":"NASH: Novel therapeutic strategies targeting ASK1 in NASH","volume":"14","author":"Schuster","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/ni1200","article-title":"ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity","volume":"6","author":"Matsuzawa","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_137","first-page":"e123694","article-title":"ASK1 inhibition reduces cell death and hepatic fibrosis in an Nlrp3 mutant liver injury model","volume":"5","author":"Geisler","year":"2020","journal-title":"JCI Insight"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/j.jhep.2016.02.002","article-title":"Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis","volume":"64","author":"Xiang","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"eadx0368","DOI":"10.1126\/scitranslmed.adx0368","article-title":"Anti-FAP CAR T cells produced in vivo reduce fibrosis and restore liver homeostasis in metabolic dysfunction-associated steatohepatitis","volume":"18","author":"Yashaswini","year":"2026","journal-title":"Sci. Transl. Med."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"102047","DOI":"10.1016\/j.xcrm.2025.102047","article-title":"Treatment of IL-18-binding protein biologics suppresses fibrotic progression in metabolic dysfunction-associated steatohepatitis","volume":"6","author":"Kim","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/hep.31622","article-title":"Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH","volume":"73","author":"Loomba","year":"2021","journal-title":"Hepatology"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jhep.2022.04.003","article-title":"Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial","volume":"77","author":"Alkhouri","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.cgh.2021.12.044","article-title":"Fenofibrate Mitigates Hypertriglyceridemia in Nonalcoholic Steatohepatitis Patients Treated With Cilofexor\/Firsocostat","volume":"21","author":"Lawitz","year":"2023","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1097\/HEP.0000000000001254","article-title":"Comparison of pharmacological therapies in metabolic dysfunction-associated steatohepatitis for fibrosis regression and MASH resolution: Systematic review and network meta-analysis","volume":"82","author":"Souza","year":"2025","journal-title":"Hepatology"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1053\/j.gastro.2020.07.034","article-title":"Progression of Fatty Liver Disease in Children Receiving Standard of Care Lifestyle Advice","volume":"159","author":"Xanthakos","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"e150996","DOI":"10.1172\/JCI150996","article-title":"Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease","volume":"131","author":"Cohen","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1056\/NEJMoa2208601","article-title":"Once-Weekly Semaglutide in Adolescents with Obesity","volume":"387","author":"Weghuber","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1111\/liv.15025","article-title":"Zonation in NASH\u2014A key paradigm for understanding pathophysiology and clinical outcomes","volume":"41","author":"Steinman","year":"2021","journal-title":"Liver Int."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1002\/hep.32570","article-title":"Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children","volume":"77","author":"Goyal","year":"2023","journal-title":"Hepatology"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1002\/hep4.1955","article-title":"Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17-beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms","volume":"6","author":"Hudert","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/d41573-026-00043-3","article-title":"In vivo CAR-T cells target fibrogenic cells in MASH","volume":"25","author":"Villanueva","year":"2026","journal-title":"Nat. Rev. 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