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Nrf2 attenuates ferroptosis-mediated IIR-ALI by modulating TERT and SLC7A11
Hui Dong1, Yangyang Xia1, Shanliang Jin1
1Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, China.
Abstract:
Acute lung injury (ALI) carries a mortality rate of ~50% and is a hot topic in the world of critical illness research. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical modulator of intracellular oxidative homeostasis and serves as an antioxidant. The Nrf2-related anti-oxidative stress is strongly associated with ferroptosis suppression. Meanwhile, telomerase reverse transcriptase (TERT), the catalytic portion of the telomerase protein, is reported to travel to the mitochondria to alleviate ROS. In our study, we found that TERT was significantly reduced in lung tissue of Nrf2-/- mice in the model of intestinal ischemia/reperfusion-induced acute lung injury (IIR-ALI). In addition, MDA levels showed marked increase, whereas GSH and GPX4 levels fell drastically in ALI models. Moreover, typical-related structural changes were observed in the type II alveolar epithelial cells in the IIR model. We further employed the scanning transmission X-ray microscopy (STXM) to examine Fe levels and distribution within cells. Based on our observations, massive aggregates of Fe were found in the MLE-12 cells upon OGD/R (oxygen and glucose deprivation/reperfusion) induction. Additionally, Nrf2 silencing dramatically reduced TERT and SLC7A11 levels, and further exacerbated cellular injuries. In contrast, TERT-overexpressing cells exhibited marked elevation in SLC7A11 levels and thereby inhibited ferroptosis. Collectively, these data suggest that Nrf2 can negatively regulate ferroptosis via modulation of TERT and SLC7A11 levels. The conclusion from this study brings insight into new candidates that can be targeted in future IIR-ALI therapy.
Insights
Nuclear factor erythroid 2-related factor 2 (Nrf2) protects against ferroptosis in acute lung injury by regulating telomerase reverse transcriptase (TERT) and SLC7A11. This finding offers potential therapeutic targets for acute lung injury.
Area of Science:
- Biomedical Research
- Cellular Biology
- Critical Care Medicine
Background:
- Acute lung injury (ALI) has a high mortality rate and is a significant research focus.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of oxidative stress and antioxidant defense.
- Nrf2-mediated antioxidant stress is linked to ferroptosis suppression, a regulated cell death pathway.
Purpose of the Study:
- To investigate the role of Nrf2 in regulating ferroptosis during intestinal ischemia/reperfusion-induced acute lung injury (IIR-ALI).
- To explore the relationship between Nrf2, telomerase reverse transcriptase (TERT), and SLC7A11 in the context of IIR-ALI.
- To identify potential therapeutic targets for IIR-ALI.
Main Methods:
- Utilized Nrf2 knockout mice and in vitro cell models (MLE-15 cells) subjected to oxygen and glucose deprivation/reperfusion (OGD/R).
- Assessed oxidative stress markers (MDA, GSH, GPX4) and cellular morphology.
- Employed scanning transmission X-ray microscopy (STXM) to analyze iron (Fe) levels and distribution.
- Investigated the effects of Nrf2 silencing and TERT overexpression on cellular injury and ferroptosis markers.
Main Results:
- TERT levels were significantly reduced in lung tissue of Nrf2 knockout mice with IIR-ALI.
- ALI models showed increased MDA and decreased GSH and GPX4 levels, with characteristic type II alveolar epithelial cell damage.
- STXM revealed massive iron aggregates in MLE-12 cells after OGD/R.
- Nrf2 silencing decreased TERT and SLC7A11, exacerbating injury, while TERT overexpression increased SLC7A11 and inhibited ferroptosis.
Conclusions:
- Nrf2 plays a crucial role in mitigating ferroptosis during IIR-ALI.
- Nrf2 negatively regulates ferroptosis through the modulation of TERT and SLC7A11 expression.
- Targeting Nrf2, TERT, or SLC7A11 may offer novel therapeutic strategies for IIR-ALI.
