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KLK1 expression is reduced in colitis, and its potential role in the intestinal mucosal barrier is still unclear. Here, KLK1 is investigated whether a supplement can reduce colitis and colorectal carcinogenesis. This study investigated KLK1's protective function in intestinal barrier integrity using Dextran Sulfate Sodium Salt (DSS) \/ Azoxymethane (AOM)\u2010DSS\u2010induced colitis\/CAC models, Apc\u2010deficient mice, and human clinical samples. KLK1\u2010AAV2 knockdown mice exhibited exacerbated colitis symptoms, including severe diarrhea and impaired mucosal barrier markers, while KLK1 levels are notably reduced in ulcerative colitis patients and colorectal cancer specimens. Mechanistically, bradykinin receptor B1 (B1R) upregulation in CAC models activated extracellular matrix pathways, driving fibroblast phenotypic shifts that disrupt stromal homeostasis. Crucially, KLK1 supplementation reversed these pathological changes, demonstrating its dual role in maintaining epithelial barrier function and regulating fibroblast\u2010ECM interactions. These findings position KLK1 as a potential therapeutic target for colitis and CRC chemoprevention, offering novel insights into IBD pathogenesis through its modulation of mucosal protection and stromal remodeling processes.<\/jats:p>","DOI":"10.1002\/advs.202507063","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T03:53:20Z","timestamp":1756266800000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["KLK1 as an Epithelial\u2010Specific Brake Inhibits Colorectal Tumorigenesis by Suppressing B1R\u2010Mediated Fibroblast Phenotypic Transition"],"prefix":"10.1002","volume":"12","author":[{"given":"Lisha","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital School of Life Sciences Chemistry and Biomedicine Innovation Center Nanjing University  163 Xianlin Avenue Nanjing Jiangsu 210023 P. R. 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