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journal article·2025-11Open access

KLK1 as an Epithelial‐Specific Brake Inhibits Colorectal Tumorigenesis by Suppressing B1R‐Mediated Fibroblast Phenotypic Transition

Lisha Zhou, Meijing Wang, Shunji Liu, Limei Gu, Shijia Liu, Qianming Du, Tianyi Zhang, Yinuo Ma, Lixin Zhao, Jiaming Wang, Qiang Xu, Tingsheng Ling, Haibo Cheng, Hongqi Chen, Yang Sun

Advanced Science· Volume 12· Issue 42
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Source abstract

Abstract

Abstract Inflammatory bowel disease (IBD) is increasing worldwide, and the persistence of chronic inflammation may lead to colitis‐associated colorectal cancer (CAC). 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)‐DSS‐induced colitis/CAC models, Apc‐deficient mice, and human clinical samples. KLK1‐AAV2 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‐ECM 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.
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Research context

OpenAlex topics: Kruppel-like factors research · Cancer-related gene regulation · Iron Metabolism and Disorders

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

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. China

Institute of Structural Pharmacology & TCM Chemical Biology College of Pharmacy Fujian University of Traditional Chinese Medicine No. 1, Qiuyang Road Fuzhou Fujian 350122 P. R. China

Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical University Xuzhou 221004 P. R. China

Digestive Endoscopy Center Affiliated Hospital of Nanjing University of Chinese Medicine Jiangsu Province Hospital of Chinese Medicine Nanjing 210029 P. R. China

The Affiliated Hospital of Nanjing University of Chinese Medicine Jiangsu Province Hospital of Chinese Medicine Nanjing Jiangsu 210029 P. R. China

General Clinical Research Center Nanjing First Hospital Nanjing Medical University Nanjing 210006 P. R. China

Department of Laboratory Medicine The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei 230026 P. R. China

Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor The First Clinical Medical College Nanjing University of Chinese Medicine 138 Xianlin Avenue Nanjing Jiangsu 210023 P. R. China

Department of General Surgery Shanghai Jiao Tong University Affiliated Sixth People's Hospital 600 Yishan Road Shanghai 200233 P. R. China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Shanghai Municipality · Key Technologies Research and Development Program

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