2. Academic Validation
  3. Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis

Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis

  • Nat Commun. 2024 Jul 12;15(1):5874. doi: 10.1038/s41467-024-50048-y.
Ying Wang # 1,  Jing Han # 1 2,  Guang Yang # 3,  Shuhui Zheng # 4,  Gaoshi Zhou # 1,  Xinjuan Liu # 5,  Xiaocang Cao # 6,  Guang Li 5,  Bowen Zhang 7,  Zhuo Xie 1,  Li Li 1,  Mudan Zhang 1,  Xiaoling Li 1,  Minhu Chen 1,  Shenghong Zhang 8 9
Affiliations

Affiliations

  • 1 Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
  • 2 Division of Gastroenterology, Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, P. R. China.
  • 3 Department of Minimally Invasive Intervention, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
  • 4 Research Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
  • 5 Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Chaoyang District, Beijing, P. R. China.
  • 6 Department of Hepato-Gastroenterology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, P. R. China.
  • 7 College of Life Sciences, Beijing Normal University, Beijing, P. R. China.
  • 8 Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China. zhshh3@mail.sysu.edu.cn.
  • 9 Division of Gastroenterology, Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, P. R. China. zhshh3@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 38997284 DOI: 10.1038/s41467-024-50048-y
Abstract

Mucus injury associated with goblet cell (GC) depletion constitutes an early event in inflammatory bowel disease (IBD). Using single-cell Sequencing to detect critical events in mucus dysfunction, we discover that the Kazal-type Serine Protease Inhibitor SPINK4 is dynamically regulated in colitic intestine in parallel with disease activities. Under chemically induced colitic conditions, the grim status in Spink4-conditional knockout mice is successfully rescued by recombinant murine SPINK4. Notably, its therapeutic potential is synergistic with existing TNF-α inhibitor infliximab in colitis treatment. Mechanistically, SPINK4 promotes GC differentiation using a Kazal-like motif to modulate EGFR-Wnt/β-catenin and -Hippo pathways. Microbiota-derived diacylated lipoprotein Pam2CSK4 triggers SPINK4 production. We also show that monitoring SPINK4 in circulation is a reliable noninvasive technique to distinguish IBD patients from healthy controls and assess disease activity. Thus, SPINK4 serves as a serologic biomarker of IBD and has therapeutic potential for colitis via intrinsic EGFR activation in intestinal homeostasis.

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