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TXNIP mediates ferroptosis in a bronchopulmonary dysplasia mouse model by regulating the SLC7A11/GPX4 pathway
Dongzhui Chen1, Feifei Yin2, Pin Yang2
1The First School of Clinical Medicine, Hainan Medical University, Haikou, 570102, Hainan, China.
Insights
Thioredoxin-interacting protein (TXNIP) promotes ferroptosis in bronchopulmonary dysplasia (BPD) by downregulating the solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) pathway. TXNIP knockdown may offer a therapeutic strategy for BPD.
Area of Science:
- Biomedical research
- Molecular biology
- Respiratory medicine
Background:
- Bronchopulmonary dysplasia (BPD) is a common respiratory disease in preterm infants.
- Ferroptosis and thioredoxin-interacting protein (TXNIP)-mediated oxidative stress are implicated in BPD pathogenesis.
- The solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) pathway is crucial for ferroptosis regulation.
Purpose of the Study:
- To investigate how TXNIP regulates the SLC7A11/GPX4 pathway in ferroptosis within a BPD model.
- To explore the therapeutic potential of targeting TXNIP in BPD.
Main Methods:
- Utilized a mouse model of hyperoxia-induced lung injury.
- Employed hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM) for pathological and morphological analysis.
- Quantified gene and protein expression (TXNIP, SLC7A11, GPX4) via qPCR and Western blotting.
- Assessed ferroptosis markers (GSH, MDA, Fe2+, GPX4 activity) and manipulated TXNIP and SLC7A11 levels using adenovirus vectors.
Main Results:
- Hyperoxia induced lung injury, increased ferroptosis markers (MDA, Fe2+), decreased antioxidants (GSH), and reduced GPX4 activity.
- TXNIP expression was upregulated, while SLC7A11 and GPX4 were downregulated in hyperoxia-exposed lungs.
- TXNIP overexpression exacerbated ferroptosis, whereas TXNIP knockdown ameliorated it.
- SLC7A11 knockdown increased ferroptosis; simultaneous knockdown of TXNIP and SLC7A11 reversed this effect.
Conclusions:
- TXNIP promotes ferroptosis in BPD by downregulating the SLC7A11/GPX4 pathway.
- Targeting TXNIP, potentially through adenovirus-mediated gene therapy, presents a promising therapeutic avenue for BPD.
Abstract:
Bronchopulmonary dysplasia (BPD) is one of the most common respiratory diseases in preterm infants. Studies have shown that ferroptosis is involved in the pathogenesis of BPD, and thioredoxin-interacting protein (TXNIP)-mediated oxidative stress also plays a role in its development. The solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway is one of the key pathways regulating ferroptosis. This study aimed to investigate the mechanism by which TXNIP regulates SLC7A11/GPX4 pathway-mediated ferroptosis in BPD. Mice were randomly divided into ten treatment groups: Air, Hyperoxia, Hyperoxia + RSL3, Hyperoxia + Ferrostatin-1, Hyperoxia + Ad-shNC, Hyperoxia + Ad-shTXNIP, Hyperoxia + Ad-vector, Hyperoxia + Ad-TXNIP, Hyperoxia + Ad-shSLC7A11, and Hyperoxia + Ad-shTXNIP + Ad-shSLC7A11. Lung tissues were collected for hematoxylin and eosin (H&E) staining to observe pathological changes, and transmission electron microscopy (TEM) was used to examine mitochondrial morphology. Real-time quantitative polymerase chain reaction (qPCR) was performed to measure the mRNA expression of TXNIP, SLC7A11, and GPX4. Western blotting was used to analyze the protein levels of TXNIP, SLC7A11, and GPX4. GPX4 activity was determined using an enzyme-linked immunosorbent assay (ELISA). Additionally, glutathione (GSH), malondialdehyde (MDA), and ferrous iron (Fe2+) levels in lung tissues were measured using corresponding detection kits. H&E staining and TEM confirmed successful modeling of lung injury after hyperoxia. MDA and Fe2+ increased, GSH decreased, and GPX4 activity declined after hyperoxia. TXNIP mRNA and protein were upregulated by hyperoxia, while SLC7A11 and GPX4 were downregulated. Ferroptosis activation exacerbated lung injury, whereas inhibition alleviated it. TXNIP overexpression using adenovirus serotype 5 (Ad5) aggravated ferroptosis in BPD, and this was ameliorated by TXNIP knockdown. Knockdown of the upstream signal SLC7A11 increased ferroptosis in BPD, and simultaneous knockdown of TXNIP and SLC7A11 reversed the ferroptosis reduction. In conclusion, in the BPD model, TXNIP expression was increased, and TXNIP promoted ferroptosis by downregulating the SLC7A11/GPX4 pathway. These findings suggest that gene therapy targeting TXNIP knockdown using adenovirus as a vector may serve as a therapeutic strategy for BPD.
