%0 Journal Article
%T Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis.
%A Wang Y
%A Han J
%A Yang G
%A Zheng S
%A Zhou G
%A Liu X
%A Cao X
%A Li G
%A Zhang B
%A Xie Z
%A Li L
%A Zhang M
%A Li X
%A Chen M
%A Zhang S
%J Nat Commun
%V 15
%N 1
%D 2024 Jul 12
%M 38997284
%F 17.694
%R 10.1038/s41467-024-50048-y
%X 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.