{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T13:13:50Z","timestamp":1783430030994,"version":"3.54.6"},"reference-count":39,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"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":["82000266"],"award-info":[{"award-number":["82000266"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018542","name":"Natural Science Foundation of Sichuan Province","doi-asserted-by":"publisher","award":["2025ZNSFSC0700"],"award-info":[{"award-number":["2025ZNSFSC0700"]}],"id":[{"id":"10.13039\/501100018542","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013365","name":"West China Hospital, Sichuan University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013365","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Redox\u2010active iron (Fe) overload and antioxidant zinc (Zn) deficiency are hallmarks of chronic liver fibrosis, yet their upstream regulatory mechanisms remain elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Here, we identify the redox\u2010sensitive metallothionein (MT) as a critical regulator in the injured liver that integrates trace\u2010metal homeostasis with Hippo\u2010Yap signalling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods &amp; Results<\/jats:title>\n                    <jats:p>\n                      MT expression was transiently induced in early\u2010stage murine and human liver fibrosis but declined sharply in advanced disease. Genetic deletion of MT in mice exacerbated CCl\n                      <jats:sub>4<\/jats:sub>\n                      \u2010induced liver injury, characterized by severe Zn depletion, pathological Fe accumulation, and aggravated fibrosis. Mechanistically, MT loss impaired the activity of Zn\u2010dependent matrix metalloproteinases and unleashed pathological Fe deposition, which amplified lipid peroxidation and oxidative damage. We revealed that MT deficiency suppressed the upstream Hippo kinase Mst1, promoting the nuclear translocation and activation of the transcriptional coactivator Yap. Crucially, pharmacological inhibition of Yap with verteporfin rescued the Fe overload and attenuated fibrosis in MT\u2010deficient livers but did not correct the Zn depletion, establishing Yap as a key downstream driver of Fe dysregulation. The analysis of human fibrotic and cirrhotic livers confirmed a conserved inverse correlation between MT levels and nuclear Yap accumulation, accompanied by severe Fe deposition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings reveal MT as a key hepatocyte integrator of trace\u2010metal homeostasis and Yap signalling and suggest that therapeutic strategies enhancing MT activity or combining Zn supplementation with Yap inhibition may offer new avenues to prevent or reverse chronic liver fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.70624","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T05:46:27Z","timestamp":1774590387000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>Metallothionein<\/scp>\n                    Safeguards Hepatic Zn\u2010Fe Homeostasis and Restrains Yap\u2010Driven Hepatic Fe Overload to Protect Against Chronic Liver Fibrosis"],"prefix":"10.1111","volume":"46","author":[{"given":"Yinrui","family":"Feng","sequence":"first","affiliation":[{"name":"Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy West China Hospital, Sichuan University  Chengdu Sichuan P. R. China"},{"name":"Regenerative Medicine Research Center, Department of Postgraduate, Sichuan University West China Hospital  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenfang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Research Center, Department of Postgraduate, Sichuan University West China Hospital  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xiao","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Research Center, Department of Postgraduate, Sichuan University West China Hospital  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yundi","family":"Liu","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Research Center, Department of Postgraduate, Sichuan University West China Hospital  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Oncology Surgery, Second Hospital of Lanzhou University Lanzhou University  Lanzhou Gansu P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Liver Surgery, Department of General Surgery and Regeneration Medicine Research Center, West China Hospital, Sichuan University  Chengdu Sichuan P. R. China"},{"name":"Department of General Surgery, Tangdu Hospital of the Air Force Medical University  Xi'an Shanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8955-416X","authenticated-orcid":false,"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University  Chengdu Sichuan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-023-00807-x"},{"key":"e_1_2_12_3_1","first-page":"139","article-title":"Fibrose: From mechanisms to medicines","volume":"176","author":"Henderson N. C.","year":"2016","journal-title":"Physiology & Behavior"},{"key":"e_1_2_12_4_1","first-page":"1094","article-title":"Biological Role of Zinc in Liver Cirrhosis: An Updated Review","volume":"11","author":"Ullah M. I.","year":"2023","journal-title":"Biomedicine"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40572-024-00463-6"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12011-023-03629-9"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2007.02.003"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/1535370214558026"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27636"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0197-0186(94)00165-Q"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1155\/ijh\/8880889"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1159\/000324282"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15352"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41232-022-00235-5"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-022-02623-w"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.12.008"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202300568R"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.12.077"},{"key":"e_1_2_12_19_1","first-page":"1","article-title":"Zinc\u2010Glutathione in Chinese Baijiu Prevents Alcohol\u2010Associated Liver Injury","volume":"9","author":"Feng Y.","year":"2023","journal-title":"Heliyon"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e35502"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2024.109697"},{"key":"e_1_2_12_22_1","first-page":"1","article-title":"The Flavonoid Quercetin Ameliorates Liver Inflammation and Fibrosis by Regulating Hepatic Macrophages Activation and Polarization in Mice","volume":"9","author":"Li X.","year":"2018","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43856-025-00780-3"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40779-023-00494-4"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.07.009"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M414361200"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30945"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1177\/153537020623100903"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu12072084"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.10.4452"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24076561"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.136496"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1177\/153537020623100203"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-011-0775-1"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2021.108802"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2024.100701"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.62903"},{"key":"e_1_2_12_39_1","first-page":"1","article-title":"Characterization of Gene Expression Profiles in HBV\u2010Related Liver Fibrosis Patients and Identification of ITGBL1 as a Key Regulator of Fibrogenesis","volume":"7","author":"Wang M.","year":"2017","journal-title":"Scientific Reports"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2025.101430"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.70624","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/liv.70624","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.70624","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:14:55Z","timestamp":1783426495000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/liv.70624"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,26]]},"references-count":39,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1111\/liv.70624"],"URL":"https:\/\/doi.org\/10.1111\/liv.70624","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,26]]},"assertion":[{"value":"2025-10-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70624"}}