{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T04:45:14Z","timestamp":1791780314377,"version":"4.3.4"},"reference-count":51,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272975"],"award-info":[{"award-number":["82272975"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82573249"],"award-info":[{"award-number":["82573249"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Metabolic dysfunction\u2010associated steatohepatitis (MASH) is driven by nutrient stress through incompletely defined epigenetic mechanisms. This study demonstrates that lipid stress activates the hexosamine biosynthesis pathway (HBP), elevating\n                    <jats:italic>O<\/jats:italic>\n                    \u2010linked \u03b2\u2010N\u2010acetylglucosamine (\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAc) modification of the N6\u2010methyladenosine (m6A) demethylase fat mass and obesity\u2010associated protein (FTO) at Ser195. This post\u2010translational modification recruits the deubiquitinase ubiquitin\u2010specific peptidase 20 (USP20), displaces the E3 ligase F\u2010box and WD repeat domain containing 7 (FBXW7), and enhances FTO protein stability and m6A demethylase activity.\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAc\u2010dependent FTO activation removes m6A from Harvey rat sarcoma viral oncogene homolog (\n                    <jats:italic>HRAS<\/jats:italic>\n                    ) mRNA, evades YTH N6\u2011methyladenosine RNA binding protein 2 (YTHDF2)\u2011mediated degradation, and prolongs transcript half\u2010life. Subsequent HRAS upregulation activates the PI3K\/AKT signaling pathway, driving hepatic steatosis and inflammation. Administration of a novel cell\u2010penetrating peptide (CPP) designed to block FTO\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAcylation at Ser195 effectively ameliorates MASH progression in vitro and in vivo. These findings establish FTO\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAcylation as a druggable metabolic\u2010epigenetic checkpoint in MASH pathogenesis, revealing a promising therapeutic strategy for this increasingly prevalent liver disease.\n                  <\/jats:p>","DOI":"10.1002\/advs.78218","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T03:55:38Z","timestamp":1791777338000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatic Lipid Stress Drives Metabolic Dysfunction\u2010Associated Steatohepatitis Progression through FTO\n                    <i>O<\/i>\n                    \u2010GlcNAcylation\u2010Induced m6A Demethylation of\n                    <i>HRAS<\/i>"],"prefix":"10.1002","author":[{"given":"Jia\u2010Xin","family":"Yin","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis The Second Affiliated Hospital Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan\u2010Lai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis The Second Affiliated Hospital Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis The Second Affiliated Hospital Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis The Second Affiliated Hospital Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai\u2010Yang","family":"Yuan","sequence":"additional","affiliation":[{"name":"MAFLD Research Center Department of Hepatology The First Affiliated Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sui\u2010Dan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology The First Affiliated Hospital of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4984-2631","authenticated-orcid":false,"given":"Ming\u2010Hua","family":"Zheng","sequence":"additional","affiliation":[{"name":"MAFLD Research Center Department of Hepatology The First Affiliated Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0137-1247","authenticated-orcid":false,"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis The Second Affiliated Hospital Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5830-8786","authenticated-orcid":false,"given":"Ni","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis The Second Affiliated Hospital Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0148-7423","authenticated-orcid":false,"given":"Ai\u2010Long","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis The Second Affiliated Hospital Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-024-01084-2"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","unstructured":"Z. M.Younossi M.Kalligeros andL.Henry \u201cEpidemiology of Metabolic Dysfunction\u2010Associated Steatotic Liver Disease \u201dClinical and Molecular Hepatology31 no. Suppl (2025):S32\u2013S50.","DOI":"10.3350\/cmh.2024.0431"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-023-00846-4"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2025.0337"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309000"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI186425"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.r1788"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.072072399"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202402451RR"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-021-03857-z"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu11112702"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.03.017"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0030115"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.687"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2025.145642"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.09.086"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2021.01.005"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjac044"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-025-03473-2"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-024-04001-1"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhazmat.2024.134440"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI20513"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01497-6"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.1c01006"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-025-01473-z"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44576-2"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-023-02792-0"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-021-01916-0"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.12134"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-018-0034-6"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.045"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2022.120732"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04128-5"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.162"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2023-330826"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.11.022"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104714"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.50230"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.09.009"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.4c00417"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-025-02058-6"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1593243"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00450-x"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.132"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01797-1"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2024.07.014"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2023.04.038"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2302291120"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-0068-6"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-2727"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.03.006"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.78218","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.78218","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.78218","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T03:55:39Z","timestamp":1791777339000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.78218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,11]]},"references-count":51,"alternative-id":["10.1002\/advs.78218"],"URL":"https:\/\/doi.org\/10.1002\/advs.78218","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,11]]},"assertion":[{"value":"2026-01-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e78218"}}