FDX1 facilitates elesclomol-induced cuproptosis and promotes glioblastoma development via transcription factor NFKB1

Ferredoxin 1 (FDX1) played a key role in mediating elesclomol-induced cuproptosis against cancer cells. Although previous studies revealed its prognostic significance and regulatory effect on immune responses in glioblastoma, the underlying mechanisms by which FDX1 modulating tumor progression and cuproptosis remained unclear. In this study, FDX1 was either overexpressed or knocked down in glioblastoma cells. Then the impacts or modulation of FDX1 expression on tumor cell proliferation, migration, invasion, and cuproptosis upon elesclomol treatment were investigated. Bioinformatic prediction of the potential transcription factors of FDX1 was performed, among which Nuclear Factor Kappa B Subunit 1 (NFKB1) was identified and validated by dual-luciferase assay as a direct regulator binding to the FDX1 promoter. Functional experiments showed that FDX1 knockdown suppressed aggressiveness and reduced cuproptosis of glioblastoma cells, while FDX1 overexpression had the opposite effects. Knockdown of NFKB1 diminished tumor growth and attenuated cuproptosis, and these effects were partially rescued by FDX1 upregulation. In vivo, FDX1 knockdown weakened the tumor-suppressive effect of elesclomol in the intracranial xenografts. Similarly, NFKB1 knockdown significantly suppressed tumor growth in vivo, while co-overexpression of FDX1 partially reversed this effect of NFKB1 knockdown. These findings revealed that FDX1 exerted a double-edged sword effect in glioblastoma by promoting tumor progression and enhancing elesclomol-induced cuproptosis. NFKB1 functioned as a positive transcriptional regulator of FDX1 and contributed to both glioblastoma development and susceptibility to cuproptosis-based therapy.