{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T23:39:24Z","timestamp":1792453164279,"version":"4.5.0"},"reference-count":48,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["BT\/RLF\/Reentry\/58\/2017"],"award-info":[{"award-number":["BT\/RLF\/Reentry\/58\/2017"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["BT\/INF\/22\/SP43045\/2021"],"award-info":[{"award-number":["BT\/INF\/22\/SP43045\/2021"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["5\/3\/8\/55\/2020\u2010ITR"],"award-info":[{"award-number":["5\/3\/8\/55\/2020\u2010ITR"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:p>Metabolic dysfunction\u2010associated steatohepatitis\u2010driven hepatocellular carcinoma (MASH\u2010HCC) is a global clinical challenge for which there is a limited understanding of disease pathogenesis and a subsequent lack of therapeutic interventions. We previously identified that tumor necrosis factor\u2010alpha (TNF\u2010\u03b1) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNF\u2010\u03b1 converting enzyme (TACE) inhibition as a promising targeted therapy against AATF\u2010mediated steatohepatitis to hepatocarcinogenesis. A preclinical murine model that recapitulates human MASH\u2010HCC was used in the study. C57Bl\/6 mice were fed with chow diet normal water (CD) or western diet sugar water (WD) along with a low dose of carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>; 0.2\u2009\u03bcL\u00b7g<jats:sup>\u22121<\/jats:sup>, weekly) for 24\u2009weeks. TACE activity, TNF\u2010\u03b1 levels, and <jats:italic>AATF<\/jats:italic> expression were measured. The mice were treated with the TACE inhibitor Marimastat for 12\u2009weeks, followed by analyses of liver injury, fibrosis, inflammation, and oncogenic signaling. <jats:italic>In vitro<\/jats:italic> experiments using stable clones of AATF control and AATF knockdown were also conducted. We found that <jats:italic>AATF<\/jats:italic> expression was upregulated in WD\/CCl<jats:sub>4<\/jats:sub> mice, which developed severe MASH at 12\u2009weeks and advanced fibrosis with HCC at 24\u2009weeks. WD\/CCl<jats:sub>4<\/jats:sub> mice showed increased TACE activity with reduced hepatic expression of sirtuin 1 (<jats:italic>Sirt1<\/jats:italic>) and tissue inhibitor of metalloproteinase 3 (<jats:italic>Timp3<\/jats:italic>). The involvement of the SIRT1\/TIMP3\/TACE axis was confirmed by the release of TNF\u2010\u03b1, which upregulated AATF, a key molecular driver of MASH\u2010HCC. Interestingly, TACE inhibition by Marimastat reduced liver injury, dyslipidemia, <jats:italic>AATF<\/jats:italic> expression, and oncogenic signaling, effectively preventing hepatocarcinogenesis. Furthermore, Marimastat inhibited the activation of JNK, ERK1\/2, and AKT, which are key regulators of tumorigenesis in WD\/CCl<jats:sub>4<\/jats:sub> mice and in <jats:italic>AATF<\/jats:italic> control cells, but had no effect on <jats:italic>AATF<\/jats:italic> knockdown cells. This study shows that TACE inhibition prevents AATF\u2010mediated inflammation, fibrosis, and oncogenesis in MASH\u2010HCC, offering a potential target for therapeutic intervention.<\/jats:p>","DOI":"10.1002\/1878-0261.13646","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T09:31:25Z","timestamp":1711963885000},"page":"1940-1957","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["<scp>TACE<\/scp> inhibition: a promising therapeutic intervention against <scp>AATF<\/scp>\u2010mediated steatohepatitis to hepatocarcinogenesis"],"prefix":"10.1002","volume":"18","author":[{"given":"Akshatha N.","family":"Srinivas","sequence":"first","affiliation":[{"name":"Department of Biochemistry, CEMR Lab, JSS Medical College JSS Academy of Higher Education and Research  Mysuru India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diwakar","family":"Suresh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, CEMR Lab, JSS Medical College JSS Academy of Higher Education and Research  Mysuru India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashant M.","family":"Vishwanath","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, CEMR Lab, JSS Medical College JSS Academy of Higher Education and Research  Mysuru India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suchitha","family":"Satish","sequence":"additional","affiliation":[{"name":"Department of Pathology, JSS Medical College and Hospital JSS Academy of Higher Education and Research  Mysuru India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanna K.","family":"Santhekadur","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, CEMR Lab, JSS Medical College JSS Academy of Higher Education and Research  Mysuru India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saisudha","family":"Koka","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy Texas A&amp;M University  Kingsville TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5935-379X","authenticated-orcid":false,"given":"Divya P.","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, CEMR Lab, JSS Medical College JSS Academy of Higher Education and Research  Mysuru India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000520"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0144-8"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.601710"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-023-00754-7"},{"issue":"6","key":"e_1_2_11_6_1","article-title":"The role of oxidative stress in NAFLD\u2010NASH\u2010HCC transition\u2010focus on NADPH oxidases","volume":"9","author":"Gabbia D","year":"2021","journal-title":"Biomedicine"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113894"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.09.020"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2020.100167"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.08.012"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1479"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.627424"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13679-023-00519-y"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevEukarGeneExpr.v20.i2.10"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23250"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0025587"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30346"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30141"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-9-457"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M309811200"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-017-0054-6"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306694200"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1130380"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2000.9915"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.03.011"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24043244"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0000000000001033"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30418"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-010-0019-9"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-022-00910-2"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.2337\/db09-0280"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)01031-X"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.19370"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802917105"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1177\/20420188221145549"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/8543763"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0145-7"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10238\u2010023\u201001014\u20103"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0043-118666"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgg.2021.09.009"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/9673537"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2014.09.017"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.3109\/10409231003628015"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2010.03.064"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1451-3"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.10.079"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6606017"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011256"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(97)00023-5"}],"container-title":["Molecular Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.13646","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T06:36:22Z","timestamp":1723098982000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/1878-0261.13646"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4]]},"references-count":48,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["10.1002\/1878-0261.13646"],"URL":"https:\/\/doi.org\/10.1002\/1878-0261.13646","archive":["Portico"],"relation":{},"ISSN":["1574-7891","1878-0261"],"issn-type":[{"value":"1574-7891","type":"print"},{"value":"1878-0261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4]]},"assertion":[{"value":"2023-09-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}