التفاصيل البيبلوغرافية
| العنوان: |
O-GlcNAcylation attenuates ischemia-reperfusion-induced pulmonary epithelial cell ferroptosis via the Nrf2/G6PDH pathway. |
| المؤلفون: |
Yang, Liuqing1,2,3 (AUTHOR), Tang, Hexiao4 (AUTHOR), Wang, Jin1,2,3 (AUTHOR), Xu, Dawei1 (AUTHOR), Xuan, Rui1 (AUTHOR), Xie, Songping5 (AUTHOR) songping0428@126.com, Xu, Pengfei6 (AUTHOR) dyxufei@sina.com, Li, Xinyi1,2,3 (AUTHOR) lxy08272021@126.com |
| المصدر: |
BMC Biology. 2/4/2025, Vol. 23 Issue 1, p1-23. 23p. |
| مصطلحات موضوعية: |
*NICOTINAMIDE adenine dinucleotide phosphate, *ADULT respiratory distress syndrome, *PENTOSE phosphate pathway, *LIFE sciences, *GLUCOSE-6-phosphate dehydrogenase |
| مستخلص: |
Background: Lung ischemia–reperfusion (I/R) injury is a common clinical pathology associated with high mortality. The pathophysiology of lung I/R injury involves ferroptosis and elevated protein O-GlcNAcylation levels, while the effect of O-GlcNAcylation on lung I/R injury remains unclear. This research aimed to explore the effect of O-GlcNAcylation on reducing ferroptosis in pulmonary epithelial cells caused by I/R. Results: First, we identified O-GlcNAc transferase 1 (Ogt1) as a differentially expressed gene in lung epithelial cells of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients, using single-cell sequencing, and Gene Ontology analysis (GO analysis) revealed the enrichment of the ferroptosis process. We found a time-dependent dynamic alteration in lung O-GlcNAcylation during I/R injury. Proteomics analysis identified the differentially expressed proteins enriched in ferroptosis and multiple redox-related pathways based on KEGG annotation. Thus, we generated Ogt1-conditional knockout mice and found that Ogt1 deficiency aggravated ferroptosis, as evidenced by lipid reactive oxygen species (lipid ROS), malondialdehyde (MDA), Fe2+, as well as alterations in critical protein expression glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Consistently, we found that elevated O-GlcNAcylation inhibited ferroptosis sensitivity in hypoxia/reoxygenation (H/R) injury-induced TC-1 cells via O-GlcNAcylated NF-E2-related factor-2 (Nrf2). Furthermore, both the chromatin immunoprecipitation (ChIP) assay and the dual-luciferase reporter assay indicated that Nrf2 could bind with translation start site (TSS) of glucose-6-phosphate dehydrogenase (G6PDH) and promote its transcriptional activity. As an important rate-limiting enzyme in the pentose phosphate pathway (PPP), elevated G6PDH provided a mass of nicotinamide adenine dinucleotide phosphate (NADPH) to improve the redox state of glutathione (GSH) and eventually led to ferroptosis resistance. Rescue experiments proved that Nrf2 knockdown or Nrf2-T334A (O-GlcNAcylation site) mutation abolished the protective effect of ferroptosis resistance. Conclusions: In summary, we revealed that O-GlcNAcylation could protect against I/R lung injury by reducing ferroptosis sensitivity via the Nrf2/G6PDH pathway. Our work will provide a new basis for clinical therapeutic strategies for pulmonary ischemia–reperfusion-induced acute lung injury. [ABSTRACT FROM AUTHOR] |
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