Wu Anyi, Yin Nanheng, Li Zengyang, Zhang Xiaopei, Zhang Zhicheng, Zhong Tao, Xia Feiyu, Pan Jiaxin, Wang Delin, Liu Liang, Dong Jun
Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Neurosurgery, Jiande First People's Hospital, Hangzhou, Zhejiang, China.
Biochem Pharmacol. 2025 Jul 25;241:117186. doi: 10.1016/j.bcp.2025.117186.
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.
铁氧还蛋白1（FDX1）在介导依斯氯醇诱导的癌细胞铜死亡中起关键作用。尽管先前的研究揭示了其在胶质母细胞瘤中的预后意义及对免疫反应的调节作用，但FDX1调节肿瘤进展和铜死亡的潜在机制仍不清楚。在本研究中，在胶质母细胞瘤细胞中过表达或敲低FDX1。然后研究了FDX1表达对依斯氯醇处理后肿瘤细胞增殖、迁移、侵袭和铜死亡的影响或调节作用。对FDX1的潜在转录因子进行了生物信息学预测，其中核因子κB亚基1（NFKB1）被鉴定，并通过双荧光素酶测定法验证为与FDX1启动子结合的直接调节因子。功能实验表明，敲低FDX1可抑制胶质母细胞瘤细胞的侵袭性并降低铜死亡，而过表达FDX1则产生相反的效果。敲低NFKB1可减少肿瘤生长并减弱铜死亡，而FDX1上调可部分挽救这些作用。在体内，敲低FDX1削弱了依斯氯醇在颅内异种移植瘤中的抑瘤作用。同样，敲低NFKB1在体内显著抑制肿瘤生长，而同时过表达FDX1可部分逆转敲低NFKB1的这种作用。这些发现表明，FDX1在胶质母细胞瘤中通过促进肿瘤进展和增强依斯氯醇诱导的铜死亡发挥双刃剑作用。NFKB1作为FDX1的正转录调节因子，对胶质母细胞瘤的发展和基于铜死亡的治疗易感性均有贡献。
