2. Academic Validation
  3. IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis

IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis

  • Nat Commun. 2024 May 15;15(1):4114. doi: 10.1038/s41467-024-48330-0.
Dadi Jiang # 1,  Youming Guo # 2,  Tianyu Wang 2 3,  Liang Wang 2,  Yuelong Yan 4,  Ling Xia 2,  Rakesh Bam 5,  Zhifen Yang 5,  Hyemin Lee 4,  Takao Iwawaki 6,  Boyi Gan 3 4,  Albert C Koong 7 8
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. djiang2@mdanderson.org.
  • 2 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 4 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
  • 6 Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan.
  • 7 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ACKoong@mdanderson.org.
  • 8 The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA. ACKoong@mdanderson.org.
  • # Contributed equally.
PMID: 38750057 DOI: 10.1038/s41467-024-48330-0
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.

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