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IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis

Author

Listed:
  • Dadi Jiang

    (The University of Texas MD Anderson Cancer Center)

  • Youming Guo

    (The University of Texas MD Anderson Cancer Center)

  • Tianyu Wang

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences)

  • Liang Wang

    (The University of Texas MD Anderson Cancer Center)

  • Yuelong Yan

    (The University of Texas MD Anderson Cancer Center)

  • Ling Xia

    (The University of Texas MD Anderson Cancer Center)

  • Rakesh Bam

    (Stanford University School of Medicine)

  • Zhifen Yang

    (Stanford University School of Medicine)

  • Hyemin Lee

    (The University of Texas MD Anderson Cancer Center)

  • Takao Iwawaki

    (Kanazawa Medical University)

  • Boyi Gan

    (The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
    The University of Texas MD Anderson Cancer Center)

  • Albert C. Koong

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences)

Abstract

Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α’s endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is evolutionarily conserved. Genetic deficiency and pharmacological inhibition of IRE1α have similar effects in inhibiting ferroptosis and reducing renal ischemia–reperfusion injury in mice. Our findings reveal a previously unidentified role of IRE1α to regulate ferroptosis and suggests inhibition of IRE1α as a promising therapeutic strategy to mitigate ferroptosis-associated pathological conditions.

Suggested Citation

  • Dadi Jiang & Youming Guo & Tianyu Wang & Liang Wang & Yuelong Yan & Ling Xia & Rakesh Bam & Zhifen Yang & Hyemin Lee & Takao Iwawaki & Boyi Gan & Albert C. Koong, 2024. "IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48330-0
    DOI: 10.1038/s41467-024-48330-0
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