Spink4, known as serine peptidase inhibitor Kazal type 4, is a secreted Kazal-type serine protease inhibitor. It is involved in modulating multiple biological pathways, such as promoting goblet cell (GC) differentiation via modulating the EGFR-Wnt/β-catenin and-Hippo pathways, and is also associated with processes like glycolysis regulation [1,3]. It has biological importance in maintaining intestinal homeostasis and is linked to various disease conditions. Mouse models have been crucial in understanding its functions.

In a Spink4-conditional knockout mouse model under chemically induced colitic conditions, the severe status was rescued by recombinant murine Spink4, indicating its therapeutic potential in colitis. This shows that Spink4 is essential for maintaining normal gut function during inflammation [1]. In colorectal cancer studies, overexpression of Spink4 in cell lines and mouse models promoted cell proliferation, metastasis, and inhibited ferroptosis, while its down-regulation was associated with poor prognosis [2,3,4,6,7]. In rectal cancer, high Spink4 expression was related to advanced clinicopathological features and poor therapeutic response in patients receiving neoadjuvant concurrent chemoradiotherapy (CCRT) [5].

In conclusion, Spink4 plays a vital role in maintaining intestinal homeostasis and is significantly associated with inflammatory bowel disease and colorectal cancer. The Spink4-conditional knockout mouse model has been instrumental in revealing its role in colitis, highlighting its potential as a serologic biomarker and therapeutic target for these diseases [1].