SPINK4 (serine peptidase inhibitor Kazal type 4) is a secreted Kazal-type serine protease inhibitor that plays critical roles in intestinal homeostasis and colorectal cancer progression. In inflammatory bowel disease (IBD), SPINK4 promotes goblet cell differentiation and maintains intestinal mucus integrity by modulating EGFR-Wnt/β-catenin and Hippo pathways using its Kazal-like motif 1. The protein is dynamically regulated in parallel with IBD disease activity and serves as a reliable noninvasive serologic biomarker for distinguishing IBD patients from healthy controls 1 2. In colorectal cancer, SPINK4 functions as a tumor suppressor, with downregulated expression associated with poor survival and higher TNM stage 3. SPINK4 inhibits CRC cell proliferation, invasion, and migration while regulating apoptosis and glycolytic metabolism by controlling key glycolytic enzymes 4. The protein expression is transcriptionally activated by ELF-1 in colon cancer cells 5. SPINK4 production is triggered by microbiota-derived diacylated lipoprotein Pam2CSK4 1, and its mRNA levels are regulated by PTGER4 signaling through HDAC4/5/7 activity in rectal epithelial cells 6. Combined with other markers, SPINK4 shows potential as a biomarker for cancer-associated thrombosis in colorectal cancer 7.