Steroid-dependent metabolic rewiring reveals novel therapeutic and imaging approaches for glioblastoma

Steroid anti-inflammatory drugs, such as dexamethasone, are routinely used to manage brain tumor?associated edema, yet their impact on brain tumor metabolism remains understudied. Here, a metabolomic screen in naïve glioblastoma cells treated with dexamethasone revealed the accumulation of N1-methylnicotinamide, a nicotinamide N-methyltransferase (NNMT) product, through glucocorticoid receptor activation. Using stable isotope-assisted metabolomics in patients with glioblastoma, we showed that nicotinamide conversion into N1-methylnicotinamide exceeds that into NAD+, leading to a ~7-fold accumulation of N1-methylnicotinamide in tumor compared to surrounding brain tissue. In orthotopic models, NNMT activity was enhanced by dexamethasone selectively in glioblastoma tumors but not in contralateral brain. Leveraging the tumor-specific activity of NNMT, we developed a novel 11C-nicotinamide?based positron emission tomography (PET) approach to visualizing glioblastoma tumors. Furthermore, our findings demonstrate that the dexamethasone-induced methionine-dependent nicotinamide methylation becomes detrimental for glioblastoma when combined with a methionine-restricted diet. These results show that steroids rewire methionine and nicotinamide metabolism, enabling the development of innovative PET imaging and metabolic therapies for glioblastoma. Dexamethasone reprograms glioblastoma nicotinamide metabolism, sensitizing tumors to methionine restriction and enabling PET.