20.500.12556/RUL-181456 Purine metabolism rewiring improves glioblastoma susceptibility to temozolomide treatment Glioblastoma (GBM) is among the deadliest cancers, characterized by poor prognosis and median survival of 12-15 months post-diagnosis. Despite aggressive therapeutic regimens, GBM treatment is still an unmet clinical need due to heterogeneity, recurrencies, and resistance. Metabolic reshaping is emerging as a critical mechanism supporting cell proliferation and sustaining chemoresistance. In this study, we explored metabolic changes induced by chemotherapy in temozolomide (TMZ)-sensitive and TMZ-resistant GBM cell lines. We found that purine levels were altered in sensitive versus resistant GBM cells, highlighting a critical role of guanosine and inosine metabolism. By using a mesenchymal-like GBM zebrafish model, we uncovered dysregulated pathways involved in purine metabolism, with a downregulation of catabolic processes. Our data indicate that combined treatment with TMZ plus guanosine and inosine increased cytotoxicity, enhancing chemotherapy effectiveness in TMZ-resistant cells. These effects correlated with alterations in mitochondrial dynamics and activity. Specifically, the combinatorial effectiveness of TMZ with guanosine and inosine was linked to Mitofusin-2 overexpression, enhancing mitochondrial fusion, typically associated with a better prognosis. Therefore, our findings suggest that purine metabolism is involved in the metabolic rewiring of TMZ-resistant cells, suggesting guanosine and inosine as potential adjuvant treatments to improve the cytotoxicity effects of chemotherapy in resistant GBM. metabolism purine glioblastoma temozolomide treatment presnova purin glioblastom temozolomid zdravljenje true false true Angleški jezik Slovenski jezik Članek v reviji 2026-04-08 11:12:45 2026-04-08 11:12:50 2026-06-18 11:47:38 0000-00-00 00:00:00 2025 0 0 12 str. iss. 1, art. 336 Vol. 16 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-092 2041-4889 10.1038/s41419-025-07667-0 237002499 RAZ_D_Aprile_Simona_2025.pdf RAZ_D_Aprile_Simona_2025.pdf 1 2D89157BD3015C0BBF163C0ED628EF46 3b0aa51353fac9fed5e8a8618999b4221dee6de31d274ead14994d678eb0c1f3 dffd2473-332b-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=231933 https://www.nature.com/articles/s41419-025-07667-0 1 ef772de0-332a-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=231929 Medicinska fakulteta 0 0 0