Metabolic Reprogramming in Neurofibromatosis Type 1: Plasma Metabolomic Signatures of MEK Inhibition Selumetinib reshapes systemic metabolism in NF1

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Abstract Background Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome driven by RAS/MAPK hyperactivation due to neurofibromin loss. Although selumetinib has changed the management of inoperable plexiform neurofibromas (PNs), the systemic metabolic changes associated with NF1, PN burden, and MEK inhibition remain poorly understood. We aimed to identify circulating metabolomic signatures associated with NF1, tumor status, and selumetinib treatment. Methods We conducted a monocentric observational study at IRCCS Istituto Giannina Gaslini (Genoa, Italy). Seventy-five participants aged 3–30 years were enrolled in four age- and sex-matched groups: NF1 patients with inoperable PNs receiving selumetinib (≥4 cycles), NF1 patients with untreated PNs, NF1 patients without tumors, and healthy controls. Peripheral plasma samples were analyzed by high-resolution mass spectrometry–based metabolomics. Data processing was performed with MS-DIAL and MS-FINDER, followed by statistical analysis with Bonferroni correction. Pathway enrichment was assessed using KEGG and MetaboAnalyst 6.0. Results Distinct metabolomic profiles emerged across groups, with the largest differences observed in selumetinib-treated patients. Compared with untreated PN patients and healthy controls, treated patients showed downregulation of pathways related to central carbon metabolism and upregulation of amino acid–related pathways. Additional alterations involved lipid metabolism and mitochondrial-associated processes. NF1 patients without tumors showed fewer metabolic changes. Overall, PN status and MEK inhibition appeared to be the main drivers of systemic metabolic variation. Conclusions Selumetinib therapy in NF1 is associated with a distinct plasma metabolic signature, consistent with reduced proliferative energy metabolism and activation of adaptive amino acid and mitochondrial pathways. These findings support metabolomic profiling as a potential noninvasive tool for treatment monitoring and biomarker development in NF1-associated tumors.