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Inhibition of thioredoxin reductase 1 sensitizes glucose-starved glioblastoma cells to disulfidptosis

Cell Death & Differentiation volume 32, pages 598–612 (2025)Cite this article

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Abstract

Disulfidptosis is a recently identified form of cell death characterized by the aberrant accumulation of cellular disulfides. This process primarily occurs in glucose-starved cells expressing higher levels of SLC7A11 and has been proposed as a therapeutic strategy for cancers with hyperactive SCL7A11. However, the potential for inducing disulfidptosis through other mechanisms in cancers remains unclear. Here, we found that inhibiting thioredoxin reductase 1 (TrxR1), a key enzyme in the thioredoxin system, induces disulfidptosis in glioblastoma (GBM) cells. TrxR1 expression is elevated in GBM with activated transcriptional coactivator with PDZ-binding motif (TAZ) and correlates with poor prognosis. TrxR1 inhibitors induced GBM cell death that can be rescued by disulfide reducers but not by ROS scavengers or inhibitors of apoptosis, ferroptosis, or necroptosis. Glucose-starved cells, but not those deprived of oxygen or glutamine, increased TrxR1 expression in an NRF2-dependent manner and were more sensitive to TrxR1 inhibition-induced cell death. The dying cells initially exhibited highly dynamic lamellipodia, followed by actin cytoskeleton collapse. This process involved the accumulation of cytosolic peroxisomes and micropinocytic caveolae, as well as small gaps in the plasma membrane. Depletion of the WAVE complex component NCKAP1 partially rescued the cells, whereas Rac inhibition enhanced cell death. In an orthotopic xenograft GBM mouse model, TrxR1 depletion inhibited tumor growth and improved survival. Furthermore, cells undergoing TrxR1 inhibition exhibited features of immunogenic cell death. Therefore, this study suggests the potential of targeting TrxR1 as a therapeutic strategy in GBM.

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Fig. 1: TXNRD1 expression is increased in GBM with activated TAZ.
Fig. 2: TAZ activation and glucose deprivation drive TrxR1 expression, while inhibition of TrxR1 further enhances cell death under glucose deprivation.
Fig. 3: TrxR1 inhibition and glucose deprivation trigger a cellular response similar to heat shock stress.
Fig. 4: Cell death induced by TrxR1 inhibition and glucose deprivation is disulfidptosis.
Fig. 5: A high level of SLC7A11 expression is not a prerequisite for disulfidptosis in the presence of AF.
Fig. 6: Distorted cellular organelles and broken plasma membrane associate with cells treated by AF under glucose deprivation.
Fig. 7: TrxR1 inhibition suppresses TAZ-driven GBM tumorigenesis.

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Data availability

The RNA-seq datasets from this study have been deposited to the Gene Expression Omnibus with the accession # GSE282324, GSE282325, and GSE282334.

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Acknowledgements

We would like to thank members of the Li laboratory for helpful discussions; Dr. Han Chen from the Transmission Electron Microscopy Core and the Microscopy Imaging Core (RRID: SCR_021200); Mr. Michael Grillo from the Microscopy Imaging Core (RRID: SCR_022526) (Leica SP8 Confocal: 1S10OD010756-01A1 CB); Dr. Wesley Raup–Konsavage from the Drug Discovery, Development and Delivery core; Mr. Nate Sheaffer, Ms. Jade Vogel, Ms. Jianhong Zhang and Mr. Joseph Bednarczyk from the Flow Cytometry Core (RRID: SCR_021134); Dr. Sirisha Pochareddy from the Genomics Sciences Core (RRID: SCR_021123); the Mass Spectrometry Core Facility (RRID: SCR_017831); Ms. Gretchen Snavely and Ms. Erin Mattern from the Comparative Medicine Histopathology Core; and Dr. Nataliya Smith, Ms. Kristin Shuler and Mr. John Graybeal from the Department of Neurosurgery’s Neuroscience Research Institute Biorepository for assistance with sample handling and IRB submissions. We acknowledge support from the National Institutes of Neurological Disorders and Stroke (R01 NS109147 and NS119547 to WL) and the Four Diamonds (to PSU).

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA

    Miaolu Tang, Kaitlyn Dirks, Soo Yeon Kim, Zhiqiang Qiu, Yan Gao, Gabrielle Peruggia, Jessica Sallavanti & Wei Li

  2. Colorado State University, Fort Collins, USA

    Kaitlyn Dirks

  3. Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA

    Dongxiao Sun

  4. Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, USA

    Wei Li

  5. Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA

    Wei Li

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Contributions

MT and WL conceived the project and designed experiments. MT performed most of the experiments under the assistance of KD, SYK, ZQ, YG, DS, GP, JS, and WL. MT and WL wrote an original manuscript. All authors provided intellectual input and edited the manuscript. WL supervised all aspects of the work.

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Correspondence to Wei Li.

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Tang, M., Dirks, K., Kim, S.Y. et al. Inhibition of thioredoxin reductase 1 sensitizes glucose-starved glioblastoma cells to disulfidptosis. Cell Death Differ 32, 598–612 (2025). https://doi.org/10.1038/s41418-024-01440-0

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