Mapping growth differentiation factor-15 (GDF15)-mediated signaling pathways in cancer: insights into its role across different cancer types.

Growth differentiation factor-15 (GDF15) is a cytokine/growth factor that belongs to the Transforming growth factor-ß (TGF-ß) protein family. The expression of GDF15 is low in most human organs under normal conditions. GDF15 is a stress-responsive cytokine primarily produced by macrophages in response to inflammatory stimuli. The altered expression of GDF15 is associated with many cancers due to the inflammation caused by the disease. GDF15 triggers the activity through its receptor Glial-derived neurotrophic factor-family receptor α-like (GFRAL) and mediates multiple downstream signaling cascades, which are involved in the progression of cancers. Considering the biological importance of GDF15 in different cancers, we applied data mining techniques to systematically compile and analyze the signaling events associated with GDF15 using NetPath criteria. This resulted in constructing a detailed GDF15-mediated signaling pathway map, enhancing our understanding of its molecular mechanisms in cancer. Furthermore, proteins linked to colorectal and breast cancer identified in our pathway map were cross-referenced with established cancer pathway databases to identify unannotated proteins, highlighting gaps in the current annotations. To investigate potential therapeutic strategies, we performed molecular docking simulations and identified Vitisifuran B as a novel inhibitor that could block the GDF15-GFRAL interaction. These findings suggest that Vitisifuran B could effectively modulate GDF15 signaling, offering a promising avenue for cancer therapeutics. This study underscores the power of computational approaches, such as data mining and molecular docking, in enhancing our understanding of GDF15 signaling in cancer and identifying potential inhibitors for therapeutic development.