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

Ying Wang, Jing Han, Guang Yang, Shuhui Zheng, Gaoshi Zhou, Xinjuan Liu, Xiaocang Cao, Guang Li, Bowen Zhang, Zhuo Xie, Li Li, Mudan Zhang, Xiaoling Li, Minhu Chen and Shenghong Zhang ()
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Ying Wang: Sun Yat-sen University
Jing Han: Sun Yat-sen University
Guang Yang: Sun Yat-sen University Cancer Center
Shuhui Zheng: Sun Yat-sen University
Gaoshi Zhou: Sun Yat-sen University
Xinjuan Liu: Chaoyang District
Xiaocang Cao: Tianjin Medical University
Guang Li: Chaoyang District
Bowen Zhang: Beijing Normal University
Zhuo Xie: Sun Yat-sen University
Li Li: Sun Yat-sen University
Mudan Zhang: Sun Yat-sen University
Xiaoling Li: Sun Yat-sen University
Minhu Chen: Sun Yat-sen University
Shenghong Zhang: Sun Yat-sen University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50048-y

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