Culture Dimensionality Governs Gallium Maltolate Response in Glioblastoma: Comparative Analyses in 2D and 3D Models

Gallium maltolate (GaM) targets iron-dependent processes in glioblastoma (GBM), but responses vary with model context. We evaluated GaM across established (A-172, U-87 MG) and patient-derived (3005, 3019, 3034, 3048, 3073) GBM lines in 2D and 3D using viability modelling (IC10/IC50/IC90), TFRC quantification, oxygen consumption rate (OCR), and PCA/PLS-DA- guided metabolomics with FDR and VIP-based selection. GaM reduced viability in all models, with a right-shift of dose-response in 3D. TFRC correlated with IC50 in 2D but not 3D, unless excluding U-87 MG from the analysis. OCR was markedly suppressed in A-172, U-87 MG, 3048, and 3073, particularly in 3D, while 3005 and 3019 were more respiration-resilient. Multivariate analyses showed treatment-dominant separation in 3005/3048, format dominance in 3019/3034, and time effects in A-172/U-87 MG/3073. A concise metabolic signature (tryptophan, methionine, uracil, allantoin) indicated coordinated perturbations in amino acid, nucleotide, and redox pathways. These findings support 3D, patient-derived systems for more predictive GaM evaluation.