Interleukin‐11 expressed in the polyp‐enriched fibroblast subset is a potential therapeutic target in Peutz‐Jeghers syndrome

Abstract Peutz‐Jeghers syndrome (PJS) is associated with early‐onset gastrointestinal polyposis caused by hereditary inactivating pathogenic variants in the tumor suppressor gene STK11 ( LKB1 ). 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‐cell RNA sequencing of PJS mouse model polyps, we here identify a polyp‐enriched 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 in vitro following acute STK11 loss. Targeted deletion of Stk11 in crypt top fibroblasts using Foxl1 ‐ Cre led to upregulation of the pCTF signature genes and later to polyposis. pCTFs displayed similarity to inflammation‐associated fibroblasts, and polyposis was exacerbated by inflammation. Cell–cell communication analysis identified interleukin 11 (IL‐11) as a potential pCTF inducer, and consistent with this, IL‐11 was required for fibroblast reprogramming toward pCTFs following STK11 loss. Importantly, a neutralizing IL‐11 antibody efficiently reduced polyp formation in a PJS model indicating a key, targetable role for IL‐11 in polyp development. Together the results characterize pCTFs as a PJS polyp‐enriched fibroblast subset and identify IL‐11 as a key mediator of fibroblast reprogramming and a potential therapeutic target in PJS. © 2025 The Pathological Society of Great Britain and Ireland.