biostudies-literatureTiek DNational Institute of Neurological Disorders and StrokeNational Institutes of Health National Cancer InstituteNIA NIH HHSNINDS NIH HHSNCI NIH HHS111769https://www.ebi.ac.uk/biostudies/studies/S-EPMC11821397biostudies-literatureUnknown28(2)Drug resistance is a major barrier to cancer therapies and remains poorly understood. Recently, non-mutational mechanisms of drug resistance have been proposed where a more plastic metabolic response can play a major role. Here, we show that upon drug resistance, glioblastoma (GBM) cells have increased oxidative stress, mitochondria function, and protein aggregation. Gamma (γ)-glutamylcyclotranserase (GGCT), an enzyme in the γ-glutamyl cycle for glutathione production, located on chromosome 7 which is commonly amplified in GBM is also increased upon resistance. We further observe that the byproduct of GGCT-pyroglutamic acid-can bind aggregating proteins and that genetic and pharmacological inhibition of GGCT prevents protein aggregation. Finally, we found increased protein aggregation, GGCiScienceOxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma.PMC11821397R21 NS126810R21 NS122375P50 CA221747K99 CA279896P30 AG072977R01 NS125318R01 NS133160K00 CA234799R01 NS115403Cheng SYMiska JHu BVassar RTiek DJamshidi PWu RHorbinski CIglesia RMcCortney KCastellani RSong XYu XCatezone AWalshon JfalseOxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma.Drug resistance is a major barrier to cancer therapies and remains poorly understood. Recently, non-mutational mechanisms of drug resistance have been proposed where a more plastic metabolic response can play a major role. Here, we show that upon drug resistance, glioblastoma (GBM) cells have increased oxidative stress, mitochondria function, and protein aggregation. Gamma (γ)-glutamylcyclotranserase (GGCT), an enzyme in the γ-glutamyl cycle for glutathione production, located on chromosome 7 which is commonly amplified in GBM is also increased upon resistance. We further observe that the byproduct of GGCT-pyroglutamic acid-can bind aggregating proteins and that genetic and pharmacological inhibition of GGCT prevents protein aggregation. Finally, we found increased protein aggregation, GGC2025-01-01T00:00:00Z2025 Feb2026-06-02T20:03:26.033Z2025-04-07T07:54:01.816ZS-EPMC118213973994996010.1016/j.isci.2025.111769