3,3'-Diindolylmethane blocks the dissemination of gastric cancer cells in the peritoneal cavity through the MFGE8-MAPK/ERK signaling pathway.

PURPOSE: Milk fat globule epidermal growth factor 8 (MFGE8) has been demonstrated to have the potential to facilitate the onset and advancement of different forms of cancer. Studies have shown that 3,3’-Diindolylmethane (DIM) has the ability to suppress GC. The precise function and operational mechanism of MFGE8 and DIM in relation to gastric cancer peritoneal dissemination (GCPD) remain poorly understood. METHODS: The role of MFGE8 in GC and GCPD was confirmed through the use of bioinformatics and patient tissues in this study. Malignant biological behavior and changes in protein expression were detected using CCK-8, colony formation, adhesion assay, transwell, and western blotting techniques. To assess the in vivo effects of MFGE8 and DIM, mice models were used. RESULTS: Based on our findings, MFGE8 could serve as a therapeutic target for GC and GCPD, while also stimulating the aggressive biological behavior of GC cells. DIM could be an effective inhibitor of the oncogenic properties of GC cells. Subsequent studies revealed that DIM was capable of inhibiting the activation of Mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated kinase (ERK) signaling pathway by blocking MFGE8, leading to the ultimate suppression of GCPD by impeding the epithelial-mesenchymal transition procedure. CONCLUSION: MFGE8 had the potential to be regarded as a marker that could provide prognostic information for GC and GCPD. Furthermore, MFGE8-MAPK/ERK pathway might be involved in the mechanism of DIM inhibiting GCPD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-025-04137-7.