IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis

Dadi Jiang (), Youming Guo, Tianyu Wang, Liang Wang, Yuelong Yan, Ling Xia, Rakesh Bam, Zhifen Yang, Hyemin Lee, Takao Iwawaki, Boyi Gan and Albert C. Koong ()
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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
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
Albert C. Koong: The University of Texas MD Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48330-0

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