Genetically Predicted 3-Methoxytyrosine Mediates the Causal Association between Fibroblast Growth Factor 21 and Glioblastoma Multiforme

<b>Background:</b> Glioblastoma multiforme (GBM) is one of the most common brain malignancies characterized by an inflammatory microenvironment and metabolic reprogramming. This study aims to investigate the causal relationship between inflammatory factors (IFs) and GBM, as well as the potential mediating effects of specific plasma metabolites. <b>Methods:</b> We used a bidirectional two-sample Mendelian randomization (MR) approach to investigate the causal associations between 91 IFs and GBM. We employed a two-step MR technique to identify significant mediators in this relationship, followed by a mediation analysis to explore and quantify the mediating effects of specific metabolites on the causal relationship between IFs and GBM. <i>In vitro</i> experiments were conducted to verify the effects of specific IF and metabolite on GBM cells. The response of cells to treatment was examined using a series of assays, including colony formation, cell proliferation, and migration assays. <b>Results:</b> Three IFs showed significant associations with GBM. Among them, fibroblast growth factor 21 (FGF21) had a protective effect against GBM [odds ratio (OR): 0.42; 95% confidence interval (CI): 0.25, 0.71; p=1.00×10^-3]. There was no strong evidence that genetically predicted GBM had an effect on FGF21 (OR: 1.04; 95% CI: 0.83, 1.31; p = 0.692). Mediation analysis identified 3-methoxytyrosine (3-MTyr) level (mediation effect of 11.50%) as a significant intermediary. The <i>in vitro</i> study demonstrated that FGF21 inhibited proliferation and migration in GBM cells, whereas 3-MTyr exerted the opposite effects. <b>Conclusion:</b> FGF21 was causally associated with a reduced risk of GBM, and this relationship is partially mediated by 3-MTyr. This identified regulatory network offers a novel avenue for further research into the pathogenic mechanisms of GBM and provides a theoretical foundation for the development of relevant therapeutic regimens.