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Matrix metalloproteinases (MMPs) are a family of zinc\u2010dependent endopeptidases that serve as central regulators of ECM homoeostasis and immune modulation in the liver. While physiological MMP activity is essential for tissue repair and immune surveillance, dysregulation of the MMP\/TIMP (tissue inhibitors of metalloproteinases) axis during viral hepatitis promotes hepatic fibrogenesis, immune evasion, and malignant transformation, positioning MMPs as both drivers of disease progression and promising therapeutic targets. This review comprehensively examines the molecular and cellular mechanisms governing MMP\/TIMP dysregulation across the spectrum of viral hepatitis, with particular focus on HCV and HBV. We address the reciprocal interactions between these viruses and MMP\/TIMP expression, the roles of MMPs in liver fibrosis, viral replication, hepatocarcinogenesis, and immunomodulation of the tumour microenvironment, and the accelerated fibrogenic mechanisms in HIV\u2013HCV and HIV\u2013HBV coinfection. The review also extends to acute viral hepatitis (HAV and HEV), where direct MMP\/TIMP data remain scarce but mechanistic and indirect ECM evidence indicate significant involvement. Finally, we critically evaluate current and emerging MMP\u2010targeted therapeutic strategies including selective inhibitors, nanoparticle delivery systems, and RNA\u2010based approaches and highlight key unresolved questions to guide future research towards disease\u2010tailored interventions against viral hepatitis\u2010driven liver damage and malignant progression.<\/jats:p>","DOI":"10.1002\/rmv.70178","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T09:13:40Z","timestamp":1782292420000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Matrix Metalloproteinases and Viral Hepatitis: A Complex Interplay Driving Liver Fibrosis, Immune Dysregulation, and Hepatocarcinogenesis"],"prefix":"10.1002","volume":"36","author":[{"given":"Zahra","family":"Heydarifard","sequence":"first","affiliation":[{"name":"Hepatitis Research Center Department of Virology Faculty of Medicine Lorestan University of Medical Sciences  Khorramabad Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somayeh","family":"Shokri","sequence":"additional","affiliation":[{"name":"Department of Virology School of Medicine Hamadan University of Medical Sciences  Hamadan Iran"},{"name":"Infectious Disease Research Center Hamadan University of Medical Sciences  Hamadan Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahab","family":"Mahmoudvand","sequence":"additional","affiliation":[{"name":"Department of Virology School of Medicine Hamadan University of Medical Sciences  Hamadan Iran"},{"name":"Infectious Disease Research Center Hamadan University of Medical Sciences  Hamadan Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Heydarifard","sequence":"additional","affiliation":[{"name":"Hepatitis Research Center Department of Virology Faculty of Medicine Lorestan University of Medical Sciences  Khorramabad Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Parnian","sequence":"additional","affiliation":[{"name":"Hepatitis Research Center Department of Virology Faculty of Medicine Lorestan University of Medical Sciences  Khorramabad Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5340-0529","authenticated-orcid":false,"given":"Habibollah","family":"Mirzaei","sequence":"additional","affiliation":[{"name":"Hepatitis Research Center Department of Virology Faculty of Medicine Lorestan University of Medical Sciences  Khorramabad Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.54394\/CJQU6666"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/s2468\u20101253(18)30056\u20106"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.04.008"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.14218\/JCTH.2025.00101"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20061358"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2019.01.004"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10050717"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jceh.2017.09.004"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2010.01.003"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2007.07.001"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584\u2010023\u201000966\u2010w"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9051313"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231810546"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.31083\/fbl27127"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408360801973244"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13092270"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9051212"},{"key":"e_1_2_14_19_1","doi-asserted-by":"crossref","unstructured":"GrossJ. 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