58 Disrupting metabolic plasticity in glioblastoma stem-like cells via FABP7 inhibition and DHA supplementation

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Abstract Introduction Glioblastoma (GBM) is a brain cancer with high recurrence and poor remission rates despite intensive therapies. Treatment resistance is attributed to GBM stem-like cells (GSCs), which display high metabolic plasticity to adapt to environmental and therapeutic stress. GSCs express high levels of fatty acid-binding protein 7 (FABP7), which facilitates intracellular lipid transport. FABP7 binds docosahexaenoic acid (DHA), a polyunsaturated fatty acid with anti-tumorigenic properties in GSCs. However, the GBM microenvironment is relatively low in DHA, and high FABP7 expression under these conditions contributes to an aggressive phenotype. Methods This study examines whether FABP7 inhibition and DHA supplementation disrupt metabolic plasticity in GSCs. We performed untargeted metabolomics and lipidomics in patient-derived GSCs, followed by high-resolution respirometry to assess changes in energy production. Metabolic shifts were further validated by measuring key genes and proteins involved in energy and lipid metabolism. Results Metabolomics revealed depletion of amino acids following DHA supplementation, an effect further enhanced by FABP7 inhibition. This was accompanied by increased expression of amino acid metabolism genes, suggesting a shift towards amino acids for energy production when FABP7 function is impaired. Consistently, respirometry demonstrated that FABP7 inhibition shifted mitochondrial respiration toward NADH oxidation, a key entry point for amino acid-derived substrates. Lipidomics revealed an FABP7-dependent increase in DHA-containing cholesterol esters upon DHA supplementation. We observed an FABP7-dependent decrease in the expression of ABCA1, a cholesterol efflux protein, upon DHA supplementation. As ABCA1 correlates with poor prognosis and exhibits drug efflux properties, this downregulation in ABCA1 suggests a mechanism for the anti-tumorigenic properties of DHA. Conclusion We show alterations in amino acid and lipid metabolism following FABP7 inhibition and DHA supplementation, highlighting metabolic vulnerabilities that may be therapeutic targets in glioblastoma.