IRE1α Determines Ferroptosis Sensitivity Through Regulation of Glutathione Synthesis

Authors

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

Publication Date

5-15-2024

Journal

Nature Communications

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.

Keywords

Animals, Humans, Male, Mice, Amino Acid Transport System y+, Cell Line, Tumor, Endoribonucleases, Ferroptosis, Glutamate-Cysteine Ligase, Glutathione, Mice, Inbred C57BL, Mice, Knockout, Protein Serine-Threonine Kinases, Reperfusion Injury, Unfolded Protein Response

Comments

Supplementary Materials

PMID: 38750057