| First Author | Jiang D | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 4114 |
| PubMed ID | 38750057 | Mgi Jnum | J:361969 |
| Mgi Id | MGI:7640837 | Doi | 10.1038/s41467-024-48330-0 |
| Citation | Jiang D, et al. (2024) IRE1alpha determines ferroptosis sensitivity through regulation of glutathione synthesis. Nat Commun 15(1):4114 |
| abstractText | Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1alpha), 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 IRE1alpha gain resistance to ferroptosis, while enhanced IRE1alpha expression promotes sensitivity to ferroptosis. Mechanistically, IRE1alpha'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 IRE1alpha is independent of its role in regulating the UPR and is evolutionarily conserved. Genetic deficiency and pharmacological inhibition of IRE1alpha have similar effects in inhibiting ferroptosis and reducing renal ischemia-reperfusion injury in mice. Our findings reveal a previously unidentified role of IRE1alpha to regulate ferroptosis and suggests inhibition of IRE1alpha as a promising therapeutic strategy to mitigate ferroptosis-associated pathological conditions. |
