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Upregulation of GPX4 drives ferroptosis resistance in scleroderma skin fibroblasts
Fali Zhang1, Yu Xiao2, Zhongzhou Huang2
1Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Abstract:
The pathogenesis of systemic sclerosis (SSC) fibrosis involves the rapid proliferation of skin fibroblasts, and current anti-fibrotic treatments are limited. This study investigated the relationship between ferroptosis and SSC skin fibroblasts. We observed that erastin-induced ferroptosis was suppressed in SSC fibroblasts. RSL3, a direct inhibitor of Glutathione Peroxidase 4 (GPX4), significantly reduced the viability of the fibroblasts, and upregulation of GPX4 in the SSC fibroblasts contributed to ferroptosis resistance. Furthermore, we demonstrated that transferrin receptor 1 (TfR1) was a crucial transporter for iron deposition in the fibroblasts. Collectively, our results highlight that GPX4 inhibition could enhance the sensitivity to ferroptosis by SSC fibroblasts, which showed distinct characteristics of iron metabolism that were not observed in normal fibroblasts in this study. Taken together, these results suggest that targeting ferroptosis could be a therapeutic strategy for the treatment of SSC.
Insights
Systemic sclerosis (SSC) fibroblasts resist ferroptosis due to high Glutathione Peroxidase 4 (GPX4). Inhibiting GPX4 and targeting iron metabolism offers a potential therapeutic strategy for SSC fibrosis.
Area of Science:
- Biochemistry
- Cell Biology
- Medical Research
Background:
- Systemic sclerosis (SSC) is characterized by fibrosis due to rapid skin fibroblast proliferation.
- Current anti-fibrotic treatments for SSC are limited in efficacy.
Purpose of the Study:
- To investigate the role of ferroptosis in systemic sclerosis (SSC) skin fibroblasts.
- To explore potential therapeutic targets related to ferroptosis in SSC.
Main Methods:
- Investigated erastin-induced ferroptosis in SSC fibroblasts.
- Utilized RSL3, a Glutathione Peroxidase 4 (GPX4) inhibitor, to assess fibroblast viability.
- Examined the expression of GPX4 and transferrin receptor 1 (TfR1).
Main Results:
- SSC fibroblasts exhibited suppressed erastin-induced ferroptosis.
- Upregulated GPX4 in SSC fibroblasts contributed to resistance to ferroptosis.
- Transferrin receptor 1 (TfR1) was identified as a key iron transporter in these cells.
- GPX4 inhibition increased ferroptosis sensitivity in SSC fibroblasts.
Conclusions:
- SSC fibroblasts display unique iron metabolism characteristics contributing to ferroptosis resistance.
- Targeting GPX4 and iron metabolism pathways presents a promising therapeutic strategy for systemic sclerosis.
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