O-GlcNAcylation attenuates ischemia-reperfusion-induced pulmonary epithelial cell ferroptosis via the Nrf2/G6PDH pathway.
Summary
O-GlcNAcylation dynamically increases during lung I/R and limits epithelial ferroptosis via the Nrf2/G6PDH pathway. Ogt1 deficiency exacerbates ferroptosis markers in vivo, supporting O-GlcNAc-dependent cytoprotection in ALI/ARDS contexts.
Key Findings
- Single-cell analyses in ALI/ARDS identified Ogt1 dysregulation and ferroptosis enrichment in epithelial cells.
- Lung O-GlcNAcylation changes dynamically during I/R; proteomics links to ferroptosis and redox pathways.
- Ogt1 conditional knockout aggravates ferroptosis markers in vivo; protection operates via Nrf2/G6PDH.
Clinical Implications
Targeting O-GlcNAc cycling or activating Nrf2/G6PDH may mitigate lung I/R injury and ALI/ARDS susceptibility to ferroptosis; pharmacologic modulators could be explored perioperatively (e.g., transplantation) or in shock states.
Why It Matters
Identifies a glyco-redox axis (O-GlcNAc–Nrf2/G6PDH) controlling ferroptosis in lung injury, offering a mechanistic basis for novel therapeutic strategies.
Limitations
- Preclinical model; clinical validation and pharmacologic modulation of O-GlcNAc/Nrf2/G6PDH are not yet demonstrated.
- Focus on epithelial cells; contributions from other lung cell types require further study.
Future Directions
Test pharmacologic O-GlcNAc modulators and Nrf2/G6PDH activators in lung I/R and ARDS models; validate human tissue signatures and identify therapeutic windows.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- IV - Preclinical mechanistic study using conditional knockout mice and multi-omics analyses.
- Study Design
- OTHER