{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:38:48Z","timestamp":1791826728490,"version":"4.3.4"},"reference-count":97,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T00:00:00Z","timestamp":1739750400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Metabolic dysfunction\u2010associated steatotic liver disease (MASLD) is a systemic disease with insulin resistance at its core. It affects one\u2010third of the world population. Fibroblast growth factor (FGF21)\u2010based therapies are effective in lowering hepatic fat content and fibrosis resolution; yet, its molecular functions remain uncertain. To gain insight into FGF21 mode of action (MoA), we investigated the transcriptomes of MASLD liver biopsies in relation to FGF21 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We compared <jats:italic>N<\/jats:italic>\u00a0=\u00a066 healthy controls with 396 MASLD patients and considered clinical characteristics relative to NAS\u00a0disease activity scores (steatosis, lobular inflammation and ballooning), fibrosis grades and sex. We performed comparative genomics to identify FGF21\u2010responsive DEGs, utilised information from FGF21\u2010transgenic and FGF21\u2010knockout mice and evaluated DEGs following FGF21 treatment of MASLD animal models. Eventually, we explored 188 validated FGF21 targets, and for \u226510 patients showing the same changes, we constructed MASLD\u2010associated networks to determine the effects of FGF21 in reverting metabolic dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified patients with increased 30% (<jats:italic>N<\/jats:italic>\u00a0=\u00a0117), decreased 40% (<jats:italic>N<\/jats:italic>\u00a0=\u00a0159) or unchanged 30% (<jats:italic>N<\/jats:italic>\u00a0=\u00a0120) FGF21 expression, and the differences are caused by changes in FGF21 transcriptional control with ATF4 functioning as a key regulator. Based on comparative genomics, we discovered molecular circuitries of FGF21 in MASLD, notably FGF21\u2010dependent induction of autophagy and oxidative phosphorylation\/mitochondrial respiration. Conversely, FGF21 repressed hepatic glycogen\u2010storage, its glucose release and gluconeogenesis, and therefore reduced glucose flux in conditions of insulin resistance. Furthermore, FGF21 repressed lipid transporters, and acetyl\u2010CoA carboxylase\u2010\u03b2 to attenuate hepatic lipid overload and lipogenesis. Strikingly, FGF21 dampened immune response by repressing complement factors, MARCO, CD163, MRC1\/CD206, CD4, CD45 and pro\u2010inflammatory cytokine receptors. It also reverted procoagulant imbalance in MASLD, stimulated extracellular matrix degradation, repressed TGF\u03b2\u2010 and integrin\u2010signalling and lessened liver sinusoidal endothelial cell defenestration in support of fibrosis resolution.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We gained deep insight into FGF21\u2010MoA in MASLD. However, heterogeneity in FGF21 expression calls for molecular stratifications as to identify patients which likely benefit from FGF21\u2010based therapies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Performed comprehensive genomics across liver biopsies of 396 MASLD patients and identified patients with increased, decreased and unchanged FGF21 expression.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Used genomic data from FGF21 transgenic, knock\u2010out and animal MASLD models treated with synthetic FGF21 analogues to identify FGF21\u2010mode\u2010of\u2010action and metabolic networks in human MASLD.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Given the significant heterogeneity in FGF21 expression, not all patients will benefit from FGF21\u2010based therapies.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70218","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T23:50:21Z","timestamp":1739836221000},"source":"Crossref","is-referenced-by-count":8,"title":["A comparative genomic study across 396 liver biopsies provides deep insight into FGF21 mode of action as a therapeutic agent in metabolic dysfunction\u2010associated steatotic liver disease"],"prefix":"10.1002","volume":"15","author":[{"given":"Shifang","family":"Tang","sequence":"first","affiliation":[{"name":"Centre for Pharmacology and Toxicology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1558-9519","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Borlak","sequence":"additional","affiliation":[{"name":"Centre for Pharmacology and Toxicology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000004"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000780"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2024.02.001"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.04.034"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-018-0438-7"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.05.018"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14466"},{"key":"e_1_2_10_10_1","volume-title":"Madame Curie Bioscience Database [Internet]","author":"Cameron MJKD","year":"2013"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1373-2"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2020.100115"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-14-518"},{"key":"e_1_2_10_15_1","volume-title":"Practical Nonparametric Statistics","author":"Conover WJ","year":"1980"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v020.i08"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/807874"},{"issue":"1","key":"e_1_2_10_18_1","article-title":"The regulation of FGF21 gene expression by metabolic factors and nutrients","volume":"30","author":"Erickson A","year":"2016","journal-title":"Horm Mol Biol Clin Investig"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2021.04.008"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2023.1112253"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.281972.116"},{"issue":"12","key":"e_1_2_10_22_1","article-title":"Association of leptin with obesity and insulin resistance","volume":"12","author":"Kumar R","year":"2020","journal-title":"Cureus"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgad653"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI67353"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.015002"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38401-z"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241612665"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1225967"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb839"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI73939"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30941"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2016.1239679"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0541"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.03.002"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.011775"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37142-3"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.08.014"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R200011-JLR200"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.200367597"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M023382"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.09.025"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.2337\/db18-0474"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2003.11.006"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25797"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2020.154457"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature16969"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.03.007"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.9.5199"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01312"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00721"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032713-120142"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2016.05.026"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2011.00036"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00422"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.01.009"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2304286"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2016.48"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2017.11.014"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.964"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15157"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12502"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.1998.2520339.x"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8101226"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2008.03.020"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.076919"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.19.13066"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.15403\/jgld-4091"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.03.013"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.20715"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2019.06.011"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27649"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.01.004"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14384-z"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2023.05.019"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.125773"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3757"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M702376200"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00808-5"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25023"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107155"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05842-9"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abn7105"},{"key":"e_1_2_10_83_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28523"},{"key":"e_1_2_10_84_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80223"},{"key":"e_1_2_10_85_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02677-9"},{"key":"e_1_2_10_86_1","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0595"},{"key":"e_1_2_10_87_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.802541"},{"key":"e_1_2_10_88_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904187106"},{"key":"e_1_2_10_89_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008-0816"},{"key":"e_1_2_10_90_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1390453"},{"key":"e_1_2_10_91_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-024-01226-7"},{"key":"e_1_2_10_92_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00601"},{"key":"e_1_2_10_93_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00222-7"},{"key":"e_1_2_10_94_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1454142"},{"key":"e_1_2_10_95_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2007-0313"},{"key":"e_1_2_10_96_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/8695157"},{"key":"e_1_2_10_97_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2015.11.012"},{"key":"e_1_2_10_98_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2016.06.003"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.70218","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,26]],"date-time":"2025-07-26T03:46:31Z","timestamp":1753501591000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.70218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":97,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1002\/ctm2.70218"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.70218","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2]]},"article-number":"e70218"}}