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Chronic inflammation can impede the phased regulation of tissue restitution, resulting in the scarring complication of fibrosis. In inflammatory bowel disease, stromal fibroblasts have been implicated in treatment-refractory disease and fibrosis\n                    <jats:sup>2,3<\/jats:sup>\n                    ; however, their mechanisms of activation have remained undefined. Through integrative single-cell and spatial profiling of intestinal tissues from patients with inflammatory bowel disease, we uncovered a pathological cell nexus centred on inflammation-associated fibroblasts. These fibroblasts were induced by proinflammatory macrophages (\n                    <jats:italic>FCN1<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    <jats:italic>IL1B<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    ) and, in turn, produced profibrotic cytokine IL-11. We investigated the inflammation-associated fibroblast activation program at a mechanistic level using genome-wide CRISPR knockout and activation screens and identified the\u00a0transcription factor GLIS3 as a key regulator of a gene regulatory network governing expression of inflammatory and fibrotic genes. We further demonstrated that the magnitude of the GLIS3 gene expression program in intestinal biopsies could be used to stratify patients with ulcerative colitis by disease severity, and that fibroblast-specific deletion of\n                    <jats:italic>Glis3<\/jats:italic>\n                    in mice alleviated pathological features of chronic colitis. Taken together, our findings identify a critical immune\u2013stromal cell circuit that functions as a central node in the inflammation\u2013fibrosis cycle.\n                  <\/jats:p>","DOI":"10.1038\/s41586-025-09907-x","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T16:01:49Z","timestamp":1767801709000},"page":"997-1006","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Bidirectional CRISPR screens decode a GLIS3-dependent fibrotic cell circuit"],"prefix":"10.1038","volume":"650","author":[{"given":"Vladislav","family":"Pokatayev","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alok","family":"Jaiswal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8945-5997","authenticated-orcid":false,"given":"Angela R.","family":"Shih","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c5sa","family":"Segerstolpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bihua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Creasey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhua","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4005-3556","authenticated-orcid":false,"given":"Crystal","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5714-1718","authenticated-orcid":false,"given":"Chih-Hung","family":"Chou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8403-8115","authenticated-orcid":false,"given":"Daniel B.","family":"Graham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5630-5167","authenticated-orcid":false,"given":"Ramnik J.","family":"Xavier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"9907_CR1","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1038\/s41586-020-2938-9","volume":"587","author":"NC Henderson","year":"2020","unstructured":"Henderson, N. 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