SELENOI Functions as a Key Modulator of Ferroptosis Pathway in Colitis and Colorectal Cancer

Author:

Huang Xin12,Yang Xu3,Zhang Mingxin3,Li Tong12,Zhu Kongdi12,Dong Yulan4,Lei Xingen5,Yu Zhengquan3,Lv Cong12,Huang Jiaqiang12ORCID

Affiliation:

1. Key Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing 100193 China

2. Beijing Advanced Innovation Center for Food Nutrition and Human Health Department of Nutrition and Health China Agricultural University Beijing 100193 China

3. College of Biological Sciences China Agricultural University Beijing 100193 China

4. College of Veterinary Medicine China Agricultural University Beijing 100193 China

5. Department of Animal Science Cornell University Ithaca NY 14853 USA

Abstract

AbstractFerroptosis 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.

Funder

National Natural Science Foundation of China

National Key Research and Development Program of China

Publisher

Wiley

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