Spatial Association Between Polyamine Metabolism and Lipid Peroxidation in Different Pathological Regions of Glioblastoma.

Background: Glioblastoma is highly heterogeneous, highly invasive, and resistant to temozolomide, with an extremely low 5-year survival rate. The spatial association between polyamine metabolism and ferroptosis remains unclear. Spatial metabolic heterogeneity is a core challenge in glioblastoma treatment. Methods: In this study, 17 patients with primary or recurrent high-grade glioma were included. Spatial metabolomics (n = 9), multiplex immunofluorescence (exploratory experiment n = 10, observational experiment n = 1), flow cytometry (n = 13), and mouse orthotopic models (n = 3) were combined to analyze the characteristics of the polyamine-ferroptosis axis in the para-carcinoma, tumor, and necrotic regions. Results: Differences in the polyamine-metabolism-ferroptosis axis were observed across distinct pathological regions of glioblastoma. Regional differences in polyamine distribution were associated with regional differences that lower lipid-peroxidation signals in the tumor region and higher lipid-peroxidation signals in the necrotic region. Moreover, in glioblastoma patient specimens, lipid-peroxidation-associated signals were detected in immune-cell compartments, alongside immune-cell phenotypic features suggestive of dysfunction, which show correlation with an immunosuppressive microenvironment. At the regional level, enzymes related to polyamine metabolism, namely GLS and SMS, exhibited spatial co-localization trends with lipid-peroxidation markers. Alterations in markers of the GSH-GPX4 and FSP1 antioxidant systems were spatially associated with the tumor-region-specific lipid-peroxidation profile. Partial spatial patterns of polyamine metabolism observed in human samples were partially recapitulated in mouse orthotopic tumor models. Conclusions: Glioblastoma exhibits spatially distinct distribution of the polyamine-ferroptosis-associated molecular signature. Notable correlative spatial features include spermidine and spermine enrichment, altered regional abundance within the glutamine-glutamate metabolic axis, immune-cell lipid-peroxidation-associated signals and immune-cell-dysfunction-related phenotypes, and regional shifts in GSH-GPX4/FSP1-related markers. This study identifies potential targets and provides a correlative spatial framework for region-specific therapeutic investigation, but the establishment of the causal relationship still requires further functional verification.