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This study demonstrates group 2 innate lymphoid cells (ILC2s), key players in tissue repair, are dysfunctional in UC and experimental colitis due to disrupted endoplasmic reticulum protein processing. We show that the pro-repair function of gut ILC2s depends on the IRE1\u03b1-Xbp1 branch of unfolded protein response (UPR), supported by IL-25 and suppressed by interferon-\u03b3 (IFN-\u03b3). During colitis, loss of IL-25 and rise of IFN-\u03b3 hinder Xbp1 mRNA splicing, weakening ILC2s\u2019 ability to mediate tissue repair. Mechanistically, spliced Xbp1 drives folate-dependent one-carbon (1C) metabolism by promoting dihydrofolate reductase expression. Translationally, the 1C metabolite adenosine 5\u2032-monophosphate alleviated colitis in both ILC2-specific Xbp1 knockout and wild-type mice. Our findings highlight the UPR\u2019s role in sensing gut environment to regulate ILC2 function and suggest folate-mediated 1C metabolism as a potential target for UC therapy.<\/jats:p>","DOI":"10.1084\/jem.20250440","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T06:20:41Z","timestamp":1758694841000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Xbp1 controls the reparative function of intestinal ILC2s during colitis"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2776-5284","authenticated-orcid":true,"given":"Yanyan","family":"Cui","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0207yh398","id-type":"ROR","asserted-by":"publisher"}],"name":"Qilu Hospital of Shandong University, Advanced Medical Research Institute, Shandong University 1 Department of Gastroenterology, , 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