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SELENOI Functions as a Key Modulator of Ferroptosis Pathway in Colitis and Colorectal Cancer.
- Source :
-
Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Jul; Vol. 11 (28), pp. e2404073. Date of Electronic Publication: 2024 May 17. - Publication Year :
- 2024
-
Abstract
- Ferroptosis plays important roles both in normal physiology and multiple human diseases. It is well known that selenoprotein named glutathione peroxidase 4 (GPX4) is a crucial regulator for ferroptosis. However, it remains unknown whether other selenoproteins responsible for the regulation of ferroptosis, particularly in gut diseases. In this study, it is observed that Selenoprotein I (Selenoi) prevents ferroptosis by maintaining ether lipids homeostasis. Specific deletion of Selenoi in intestinal epithelial cells induced the occurrence of ferroptosis, leading to impaired intestinal regeneration and compromised colonic tumor growth. Mechanistically, Selenoi deficiency causes a remarkable decrease in ether-linked phosphatidylethanolamine (ePE) and a marked increase in ether-linked phosphatidylcholine (ePC). The imbalance of ePE and ePC results in the upregulation of phospholipase A2, group IIA (Pla2g2a) and group V (Pla2g5), as well as arachidonate-15-lipoxygenase (Alox15), which give rise to excessive lipid peroxidation. Knockdown of PLA2G2A, PLA2G5, or ALOX15 can reverse the ferroptosis phenotypes, suggesting that they are downstream effectors of SELENOI. Strikingly, GPX4 overexpression cannot rescue the ferroptosis phenotypes of SELENOI-knockdown cells, while SELENOI overexpression can partially rescue GPX4-knockdown-induced ferroptosis. It suggests that SELENOI prevents ferroptosis independent of GPX4. Taken together, these findings strongly support the notion that SELENOI functions as a novel suppressor of ferroptosis during colitis and colon tumorigenesis.<br /> (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)
- Subjects :
- Mice
Animals
Humans
Disease Models, Animal
Phospholipid Hydroperoxide Glutathione Peroxidase metabolism
Phospholipid Hydroperoxide Glutathione Peroxidase genetics
Signal Transduction genetics
Ferroptosis genetics
Colorectal Neoplasms metabolism
Colorectal Neoplasms genetics
Colorectal Neoplasms pathology
Selenoproteins metabolism
Selenoproteins genetics
Colitis metabolism
Colitis genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2198-3844
- Volume :
- 11
- Issue :
- 28
- Database :
- MEDLINE
- Journal :
- Advanced science (Weinheim, Baden-Wurttemberg, Germany)
- Publication Type :
- Academic Journal
- Accession number :
- 38757622
- Full Text :
- https://doi.org/10.1002/advs.202404073