Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion.

Abstract

Ferroptosis is a recently identified form of regulated cell death defined by the iron-dependent accumulation of lipid reactive oxygen species. Ferroptosis has been studied in various diseases such as cancer, Parkinson's disease, and stroke. However, the exact function and mechanism of ferroptosis in ischemia/reperfusion (I/R) injury, especially in the intestine, remains unknown. Considering the unique conditions required for ferroptosis, we hypothesize that ischemia promotes ferroptosis immediately after intestinal reperfusion. In contrast to conventional strategies employed in I/R studies, we focused on the ischemic phase. Here we verified ferroptosis by assessing proferroptotic changes after ischemia along with protein and lipid peroxidation levels during reperfusion. The inhibition of ferroptosis by liproxstatin-1 ameliorated I/R-induced intestinal injury. Acyl-CoA synthetase long-chain family member 4 (ACSL4), which is a key enzyme that regulates lipid composition, has been shown to contribute to the execution of ferroptosis, but its role in I/R needs clarification. In the present study, we used rosiglitazone (ROSI) and siRNA to inhibit ischemia/hypoxia-induced ACSL4 in vivo and in vitro. The results demonstrated that ACSL4 inhibition before reperfusion protected against ferroptosis and cell death. Further investigation revealed that special protein 1 (Sp1) was a crucial transcription factor that increased ACSL4 transcription by binding to the ACSL4 promoter region. Collectively, this study demonstrates that ferroptosis is closely associated with intestinal I/R injury, and that ACSL4 has a critical role in this lethal process. Sp1 is an important factor in promoting ACSL4 expression. These results suggest a unique and effective mechanistic approach for intestinal I/R injury prevention and treatment.

• Authors: Yang Li, Dongcheng Feng, Zhanyu Wang, Yan Zhao, Ruimin Sun, Donghai Tian, Deshun Liu, Feng Zhang, Shili Ning, Jihong Yao, Xiaofeng Tian
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 26 Issue 11 Pg. 2284-2299 (Nov 2019) ISSN: 1476-5403 [Electronic] England
• PMID: 30737476 (Publication Type: Journal Article)

Chemical References

• DNA-Binding Proteins
• Quinoxalines
• Reactive Oxygen Species
• Sp1 Transcription Factor
• Spiro Compounds
• liproxstatin-1
• Rosiglitazone
• Acsl4 protein, mouse
• Coenzyme A Ligases

Topics

• Animals
• Caco-2 Cells
• Cell Line, Tumor
• Coenzyme A Ligases (antagonists & inhibitors, genetics, metabolism)
• DNA-Binding Proteins (metabolism)
• Ferroptosis (drug effects, physiology)
• Humans
• Intestines (injuries, pathology)
• Lipid Peroxidation (physiology)
• Mice
• Mice, Inbred C57BL
• Models, Animal
• Promoter Regions, Genetic (genetics)
• Quinoxalines (pharmacology)
• Reactive Oxygen Species (metabolism)
• Reperfusion Injury (pathology)
• Rosiglitazone (pharmacology)
• Sp1 Transcription Factor (metabolism)
• Spiro Compounds (pharmacology)