# GSR Deficiency Exacerbates Oxidative Stress and Promotes Pulmonary Fibrosis

## TL;DR

Low levels of the antioxidant enzyme GSR worsen lung scarring in a deadly lung disease called IPF by increasing oxidative stress and activating fibrotic pathways.

## Contribution

This study reveals that GSR deficiency promotes pulmonary fibrosis through oxidative stress and TGF-β/Smad2 signaling activation.

## Key findings

- GSR levels are reduced in IPF patients and bleomycin-treated mice.
- GSR depletion increases epithelial-to-mesenchymal transition and fibroblast activation.
- Reduced GSR leads to lower GSH levels, higher ROS, and TGF-β/Smad2 pathway activation.

## Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder characterized by excessive scarring of lung tissue, predominantly affecting middle-aged and elderly populations. Oxidative stress plays a pivotal role in the pathogenesis of pulmonary fibrosis, disrupting redox homeostasis and driving fibrotic progression. Glutathione reductase (GSR), a key antioxidant enzyme, is essential for maintaining cellular glutathione (GSH) levels and mitigating oxidative damage. However, the specific involvement of GSR in IPF remains poorly understood. This study found that GSR levels were downregulated in IPF patients and mice treated with bleomycin (BLM). GSR knockdown enhanced epithelial-to-mesenchymal transition (EMT) in A549 cells and promoted the activation of MRC5 cells. Additionally, GSR depletion promoted cellular migration and senescence in both A549 and MRC5 cells. Mechanistically, silencing GSR in A549 and MRC5 cells led to a marked reduction in intracellular GSH levels, resulting in elevated reactive oxygen species (ROS) accumulation, thereby promoting the activation of the TGF-β/Smad2 signaling pathway. In conclusion, our findings demonstrate that GSR deficiency aggravates pulmonary fibrosis by impairing antioxidant defense mechanisms, promoting EMT, and activating fibroblasts through the TGF-β/Smad2 signaling. These findings suggest that GSR may be essential in reducing the fibrotic progression of IPF.