GSDMB interacts with IGF2BP1 to suppress colorectal cancer progression by modulating DUSP6-ERK pathway

•Aberrantly upregulated GSDMB suppresses the colorectal cancer progression.•GSDMB-mediated DUSP-ERK pathway determines cancer cell fate.•GSDMB interacts with IGF2BP1 to regulate DUSP6-ERK pathway.•Transgenic expression of epithelial GSDMB develops diminished tumorigenesis. There is growing evidence that the protein family of Gasdermins (GSDMs) play an essential role during the progression of colorectal cancer (CRC). However, it is not completely clear that how GSDMB, abundantly expressed in epithelial cells of gastrointestinal tract, regulates the tumorigenesis of CRC. A wealth of evidence linking GSDMB to the pathogenesis of cancer has come from genome-wide association studies. Here, we provide evidence that aberrantly upregulated GSDMB is responsible for suppressing the CRC progression by using in vitro cell and intestinal organoid, as well as in vivo GSDMB transgenic mice models. Mechanistically, GSDMB interacts with insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which directly binds to and recognizes the 3′-UTR of dual specificity phosphatase 6 (DUSP6) mRNA, enhances the translation of DUSP6 protein and inhibits downstream ERK phosphorylation, thereby facilitating cell death and restraining cell proliferation. Our results suggest that GSDMB has potential as a novel therapeutic target for CRC treatment.