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The molecular events driving extracellular matrix (ECM) accumulation are incompletely understood. In this study, we aimed to investigate stage-specific gene expression signatures in ALD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Liver biopsies from 50 adults with prior alcohol overuse were selected: No fibrosis (controls (F0), n\u2009=\u200910), mild\/moderate fibrosis (F1\u2013F2, n\u2009=\u200919), and advanced fibrosis\/cirrhosis (F3\u2013F4, n\u2009=\u200921). We performed multiplexed targeted profiling of 760 mRNAs, followed by analysis of differentially expressed genes (DEGs) and gene set enrichment analysis. Selected targets were validated on the protein level using immunohistochemistry. Mild\/moderate fibrosis versus controls showed 80 DEGs (p &lt; 0.01), 63 of which were downregulated. MLXIPL and FURIN, both involved in glucose and lipid metabolism, were downregulated. Pathways involved in ECM formation were enriched. Advanced fibrosis vs. controls showed 187 DEGs (p &lt; 0.01), of which 94 were upregulated. These included fibrogenic and inflammatory mediators such as TGFB1, COL1A1\/2, TIMP1, LGALS3, and S100A4. Genes involved in fatty acid, steroid, and lipid metabolism were significantly repressed. Advanced versus mild\/moderate fibrosis showed 211 DEGs (p &lt; 0.01), with an increase in TGF-\u03b2-driven ECM remodeling and inhibition of lipid and fatty-acid metabolism pathways. LGALS3 and S100A4 mRNA levels correlated with protein expression (R\u2009\u2265\u20090.41, p\u2009&lt;\u20090.01).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>ALD is characterized by early downregulation of metabolic genes and upregulation of ECM formation, followed by coordinated induction of the TGF-\u03b2-centered fibrogenic pathway and further suppression of metabolic pathways. We identified stage-specific molecular alterations associated with ALD progression and LGALS3 and S100A4 as candidate biomarkers.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11033-026-11955-z","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T11:25:58Z","timestamp":1781004358000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multiplexed targeted mRNA profiling of alcohol-related liver disease reveals stage-specific dysregulation of signaling pathways"],"prefix":"10.1007","volume":"53","author":[{"given":"Dusan","family":"Rasic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Thiele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander","family":"Krag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f6nke","family":"Detlefsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"issue":"1","key":"11955_CR1","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1186\/s12889-023-15749-x","volume":"23","author":"X Niu","year":"2023","unstructured":"Niu X, Zhu L, Xu Y, Zhang M, Hao Y, Ma L et al (2023) Global prevalence, incidence, and outcomes of alcohol related liver diseases: a systematic review and meta-analysis. 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M.T. has served as speaker and\/or consultant speaker for Echosens, Madrigal, Takeda, Novo Nordisk, Boehringer Ingelheim, Astra Zeneca, and GSK, all outside of the submitted work. Investigator-initiated research grant to institution from GSK. M.T. is co-founder of Evido. A.K. has served as speaker and\/or consultant\/advisory board for Novo Nordisk, Norgine, Boehringer Ingelheim, GSK, W4Cure, Madrigal, all outside the submitted work. A.K. received research support to institution from Astra, Siemens, Nordic Bioscience, GSK, Echosense. A.K. is board member and co-founder of Evido.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Region of Southern Denmark (project-ID: S-20120071, S-20160021, and S-20200136) and the Danish Data Protection Agency (journal-no. 20\/50661). Patients had not advocated against the use of their tissue in the Danish registry for the use of tissue in research (\u2018V\u00e6vsanvendelsesregisteret\u2019). Given the retrospective study design and the use of archival material, informed consent was waived in accordance with national regulations.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval\u00a0and informed consent"}},{"value":"During the preparation of this work, the authors used AI software (Microsoft Copilot, Microsoft) to proofread and improve the text\u2019s readability. After using this software, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Generative AI and AI-assisted technologies in the manuscript preparation process"}}],"article-number":"916"}}