Neuro-oncology · 2026
NAD(P)H: quinone oxidoreductase 1-mediated oxidative stress resistance and tumor microenvironment remodeling in glioblastoma.
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Li Yangqing, Kang Tao, Jia Zhen, Lu Chenfei, Cui Gaoyuan, Song Kefan, Yu Hang, Dixit Deobrat, Jin Fangshu, Shan Danyang, Lin Qiankun, Li Daqi, You Hao, Gu Danling, Gao Jiancheng, Shi Zhumei, Gao Wei, Lin Fan, Zhu Zhe, Wang Qianghu, Tao Weiwei, Zhang Junxia, Liang Jingshan, Zhu Zhu, You Yongping, Qian Xu, Yang Kailin, Wang Xiuxing, Rich Jeremy N, Yang Kun, Sun Luan, Li Chaojun, Zhang Qian
Аннотация
BACKGROUND: Glioblastoma (GBM) is a highly aggressive brain tumor, with glioblastoma stem cells (GSCs) occupying the pinnacle of a complex tumor microenvironment (TME), conferring therapeutic resistance. The TME plays a role in tumor development by creating a niche rich in reactive oxygen species (ROS) through oxidative stress (OS). Here, we identified NAD(P)H: quinone oxidoreductase 1 (NQO1) as an essential regulatory factor in antioxidant stress response, which is key to maintaining GSCs and the immunosuppressive TME.
METHODS: Proteomics analysis and epigenetic profiling using H3K27ac ChIP-sequencing and single-cell RNA sequencing were performed to define the high enrichment of NQO1 in GBM. In vitro and in vivo loss-of-function genetic and pharmacologic assays were conducted to evaluate the effect of NQO1 in GSC proliferation and self-renewal. Patient-derived GSCs and xenograft murine models were using to investigate the tumor-intrinsic and extrinsic mechanisms to confers resistance to OS and reprogram the immunosuppressive TME.
RESULTS: NQO1 was preferentially expressed in GSCs and regulated ROS levels, preserving the stability of nuclear Lamin B1 and inhibiting cGAS-type I interferon signaling, which helps to remodel the immunosuppressive TME. Furthermore, nuclear factor erythroid 2-related factor 2 (NRF2) transcriptionally regulates NQO1, suppressing type I interferon signaling.
CONCLUSIONS: NQO1 plays critical roles at both the cell-autonomous and cell-extrinsic levels for clinical treatment. Targeting NQO1 and its downstream signaling pathways, including β-lapachone and immune checkpoint inhibitors such as anti-PD-1 therapy, enhances our understanding of the interactions between GSCs, OS, and the TME. This offers promising new avenues for clinical intervention in GBM.
METHODS: Proteomics analysis and epigenetic profiling using H3K27ac ChIP-sequencing and single-cell RNA sequencing were performed to define the high enrichment of NQO1 in GBM. In vitro and in vivo loss-of-function genetic and pharmacologic assays were conducted to evaluate the effect of NQO1 in GSC proliferation and self-renewal. Patient-derived GSCs and xenograft murine models were using to investigate the tumor-intrinsic and extrinsic mechanisms to confers resistance to OS and reprogram the immunosuppressive TME.
RESULTS: NQO1 was preferentially expressed in GSCs and regulated ROS levels, preserving the stability of nuclear Lamin B1 and inhibiting cGAS-type I interferon signaling, which helps to remodel the immunosuppressive TME. Furthermore, nuclear factor erythroid 2-related factor 2 (NRF2) transcriptionally regulates NQO1, suppressing type I interferon signaling.
CONCLUSIONS: NQO1 plays critical roles at both the cell-autonomous and cell-extrinsic levels for clinical treatment. Targeting NQO1 and its downstream signaling pathways, including β-lapachone and immune checkpoint inhibitors such as anti-PD-1 therapy, enhances our understanding of the interactions between GSCs, OS, and the TME. This offers promising new avenues for clinical intervention in GBM.