{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T15:42:50Z","timestamp":1792338170085,"version":"4.4.0"},"reference-count":53,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:00:00Z","timestamp":1792281600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:00:00Z","timestamp":1792281600000},"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":["82370878"],"award-info":[{"award-number":["82370878"]}],"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":["82200975"],"award-info":[{"award-number":["82200975"]}],"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":["82300659"],"award-info":[{"award-number":["82300659"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003995","name":"Natural Science Foundation of Anhui Province","doi-asserted-by":"publisher","award":["2308085QH247"],"award-info":[{"award-number":["2308085QH247"]}],"id":[{"id":"10.13039\/501100003995","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 steatotic liver disease (MASLD) affects approximately one\u2010third of adults and lacks effective pharmacological therapies. Here, we identify Chromobox 2 (CBX2), a Polycomb\u2010associated chromatin regulator, as a previously unrecognized regulator of hepatic lipid homeostasis. CBX2 expression is markedly reduced in hepatocytes from patients with MASLD, multiple mouse models (\n                    <jats:italic>db\/db<\/jats:italic>\n                    ,\n                    <jats:italic>ob\/ob<\/jats:italic>\n                    , HFD, and HFHC), and steatotic hepatocytes\n                    <jats:italic>in<\/jats:italic>\n                    <jats:italic>vitro<\/jats:italic>\n                    . Hepatocyte\u2010specific CBX2 overexpression ameliorates hepatic steatosis, improves glucose metabolism, and suppresses inflammation, whereas CBX2 deficiency exacerbates these metabolic disturbances. Mechanistically, CBX2 enhances H3K4me3 enrichment at the\n                    <jats:italic>Orai1<\/jats:italic>\n                    promoter, promoting\n                    <jats:italic>Orai1<\/jats:italic>\n                    transcription and increasing intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    levels. Elevated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    activates the CaMKK2\u2010AMPK signaling pathway, leading to ACC phosphorylation, inhibition of\n                    <jats:italic>de novo<\/jats:italic>\n                    lipogenesis (FAS, ACC, and SCD\u20101), enhancement of fatty acid oxidation (PPAR\u03b1 and CPT\u20101a), and suppression of NF\u2010\u03baB\/JNK\u2010mediated inflammation. Genetic and pharmacological interventions further establish the necessity of this Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010CaMKK2\u2010AMPK axis for CBX2\u2010mediated metabolic protection. Collectively, our findings reveal a CBX2\u2010driven metabolic regulatory circuit and highlight CBX2 and its downstream signaling pathway as potential therapeutic targets for MASLD.\n                  <\/jats:p>","DOI":"10.1002\/advs.78372","type":"journal-article","created":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T15:00:52Z","timestamp":1792335652000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatocyte CBX2 Safeguards Hepatic Lipid Homeostasis by Elevating Ca\n                    <sup>2+<\/sup>\n                    \u2010CaMKK2\u2010AMPK Signaling to Counter MASLD"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2594-7148","authenticated-orcid":false,"given":"Xiang","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Metabolic Disease Research Center School of Basic Medicine Anhui Medical University  Hefei China"},{"name":"Department of Hyperbaric Oxygen The Second People's Hospital of Hefei Hefei Hospital Affiliated to Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Metabolic Disease Research Center School of Basic Medicine Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7563-0580","authenticated-orcid":false,"given":"Xiuyun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Metabolic Disease Research Center School of Basic Medicine Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Du","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Metabolism and Molecular Medicine &amp; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Fudan University Shanghai Cancer Center Shanghai Medical College of Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menglong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Metabolic Disease Research Center School of Basic Medicine Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2904-0055","authenticated-orcid":false,"given":"Kechao","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Metabolic Disease Research Center School of Basic Medicine Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Metabolic Disease Research Center School of Basic Medicine Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinrui","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Metabolic Disease Research Center School of Basic Medicine Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingya","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Metabolic Disease Research Center School of Basic Medicine Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1094-1843","authenticated-orcid":false,"given":"Xu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Division of Life Sciences and Medicine The First Affiliated Hospital of USTC University of Science and Technology of China  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenglin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery The First Affiliated Hospital of Anhui Medical University  Hefei Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4337-1517","authenticated-orcid":false,"given":"Siwei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of General Surgery The First Affiliated Hospital of Anhui Medical University  Hefei Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Metabolic Disease Research Center School of Basic Medicine Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6546-9334","authenticated-orcid":false,"given":"Gong\u2010Hong","family":"Wei","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Metabolism and Molecular Medicine &amp; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Fudan University Shanghai Cancer Center Shanghai Medical College of Fudan University  Shanghai China"},{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases Suzhou Institute of Systems Medicine Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4288-6228","authenticated-orcid":false,"given":"Yinliang","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Hyperbaric Oxygen The Second People's Hospital of Hefei Hefei Hospital Affiliated to Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5481-3873","authenticated-orcid":false,"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of General Surgery The First Affiliated Hospital of Anhui Medical University  Hefei Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7846-8127","authenticated-orcid":false,"given":"Yongsheng","family":"Chang","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Cellular Homeostasis and Disease, Key Department of Physiology and Pathophysiology, Laboratory of Immune Microenvironment and Disease (Ministry of Education) Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8402-7830","authenticated-orcid":false,"given":"Huabing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Metabolic Disease Research Center School of Basic Medicine Anhui Medical University  Hefei China"},{"name":"Department of Otorhinolaryngology Head and Neck Surgery The First Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,18]]},"reference":[{"key":"e_1_2_11_2_1","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 M. 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