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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Fibrosis is a shared feature of chronic liver, kidney and heart disease, yet no molecular signature captures the mechanisms common to these organs. We integrated human microarray, bulk and single-nucleus RNA sequencing (snRNA-seq) data across 2022 unique tissue samples to identify a conserved pan-fibrotic signature. The pan-fibrotic signature was defined in a microarray discovery cohort (n = 1051) and verified in a microarray liver (n = 325), two RNA-seq (n = 414) and four integrated snRNA-seq validation datasets (n = 69). Diagnostic models were built using five machine learning approaches in separate RNA-seq cohorts (training n = 209; liver validation n = 70; kidney validation n = 24). 492 fibrosis-associated genes were identified across organs, including 23 hallmark genes, a subset of which correlated with disease severity. A novel finding was consistent metallothionein (MT1E, MT1X) downregulation; snRNA-seq resolved cell-type-specific expression of 12 hallmark genes, including MT1E\/MT1X predominantly expressed in hepatocytes and liver sinusoidal endothelial cells. Elastic Net performed best across all three gene sets (AUROC 0.765\u20130.830), with scores correlating significantly with interstitial fibrosis and tubular atrophy (%IFTA; rho 0.58\u20130.73). This study defines a cross-organ pan-fibrotic signature, providing potential candidate therapeutic targets and biomarkers applicable across tissues affected by fibrosis.<\/jats:p>","DOI":"10.3390\/ijms27198755","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:01:19Z","timestamp":1790773279000},"page":"8755","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pan-Fibrotic Gene Expression Signature in Major Chronic Diseases by Integrative Bulk and Single-Cell Transcriptomic Analyses"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4202-7810","authenticated-orcid":false,"given":"Mayra Alejandra","family":"Jaimes-Campos","sequence":"first","affiliation":[{"name":"Department of Biomarker Research, Mosaiques Diagnostics GmbH, D-30659 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4068-9167","authenticated-orcid":false,"given":"Rafael","family":"Stroggilos","sequence":"additional","affiliation":[{"name":"Systems Biology Center, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Joost P.","family":"Schanstra","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France"},{"name":"Faculty of Health, Universit\u00e9 Toulouse III Paul-Sabatier, 31432 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3284-5713","authenticated-orcid":false,"given":"Antonia","family":"Vlahou","sequence":"additional","affiliation":[{"name":"Systems Biology Center, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Manon","family":"Brunet","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9882-5438","authenticated-orcid":false,"given":"Jean-Christophe","family":"Jonas","sequence":"additional","affiliation":[{"name":"P\u00f4le d\u2019Endocrinologie, Diab\u00e8te et Nutrition, Institut de Recherche Exp\u00e9rimentale et Clinique, Universit\u00e9 Catholique de Louvain, B-1200 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1641-1694","authenticated-orcid":false,"given":"Mohammed","family":"Bensellam","sequence":"additional","affiliation":[{"name":"P\u00f4le d\u2019Endocrinologie, Diab\u00e8te et Nutrition, Institut de Recherche Exp\u00e9rimentale et Clinique, Universit\u00e9 Catholique de Louvain, B-1200 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0323-0306","authenticated-orcid":false,"given":"Harald","family":"Mischak","sequence":"additional","affiliation":[{"name":"Department of Biomarker Research, Mosaiques Diagnostics GmbH, D-30659 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8917-2412","authenticated-orcid":false,"given":"Agnieszka","family":"Latosinska","sequence":"additional","affiliation":[{"name":"Department of Biomarker Research, Mosaiques Diagnostics GmbH, D-30659 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/s41584-019-0322-7","article-title":"Shared and Distinct Mechanisms of Fibrosis","volume":"15","author":"Distler","year":"2019","journal-title":"Nat. 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