Spink4, known as serine peptidase inhibitor Kazal type 4, is a secreted Kazal-type serine protease inhibitor. It is highly expressed in human goblet cells. Functionally, it promotes goblet cell differentiation via modulating the EGFR-Wnt/β-catenin and-Hippo pathways using a Kazal-like motif. Microbiota-derived diacylated lipoprotein Pam2CSK4 can trigger its production [1].

In colitis, Spink4-conditional knockout mice show a grim status, which can be rescued by recombinant murine Spink4. Its therapeutic potential is synergistic with the TNF-α inhibitor infliximab. This indicates that Spink4 has a role in maintaining intestinal homeostasis and treating colitis [1].

In colorectal cancer, although some studies show it is downregulated and associated with poor prognosis, in vitro and in vivo experiments demonstrate that overexpression of Spink4 promotes cell proliferation, metastasis, and inhibits ferroptosis. It also regulates glycolysis, with overexpression reducing CRC cell proliferation, invasion, and migration, and decreasing tumor volume in vivo [2,3].

In conclusion, Spink4 is crucial for goblet cell differentiation and intestinal homeostasis. Its conditional knockout mouse model has revealed its therapeutic potential in colitis. In colorectal cancer, despite its complex expression pattern, studies suggest its role in cancer cell behaviors, providing insights into the disease mechanisms and potential treatment strategies.