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Due to lack of prophylactic therapies, management of PJS polyps requires frequent surveillance. Interestingly, studies in mouse models have revealed that stromal cells drive the polyp formation, but detailed understanding of the cell types and interactions involved has been lacking. Using single\u2010cell RNA sequencing of PJS mouse model polyps, we here identify a polyp\u2010enriched crypt top fibroblast (pCTF) cluster characterized by a transcriptional signature also enriched in PJS patient polyps. The pCTF signature was also noted in primary fibroblasts\n                    <jats:italic>in vitro<\/jats:italic>\n                    following acute STK11 loss. Targeted deletion of\n                    <jats:italic>Stk11<\/jats:italic>\n                    in crypt top fibroblasts using\n                    <jats:italic>Foxl1<\/jats:italic>\n                    \u2010\n                    <jats:italic>Cre<\/jats:italic>\n                    led to upregulation of the pCTF signature genes and later to polyposis. pCTFs displayed similarity to inflammation\u2010associated fibroblasts, and polyposis was exacerbated by inflammation. Cell\u2013cell communication analysis identified interleukin 11 (IL\u201011) as a potential pCTF inducer, and consistent with this, IL\u201011 was required for fibroblast reprogramming toward pCTFs following STK11 loss. Importantly, a neutralizing IL\u201011 antibody efficiently reduced polyp formation in a PJS model indicating a key, targetable role for IL\u201011 in polyp development. Together the results characterize pCTFs as a PJS polyp\u2010enriched fibroblast subset and identify IL\u201011 as a key mediator of fibroblast reprogramming and a potential therapeutic target in PJS. \u00a9 2025 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6408","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T05:01:29Z","timestamp":1741755689000},"page":"66-80","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Interleukin\u201011 expressed in the polyp\u2010enriched fibroblast subset is a potential therapeutic target in Peutz\u2010Jeghers 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