Upregulation of GPX4 drives ferroptosis resistance in scleroderma skin fibroblasts

Fali Zhang; Yu Xiao; Zhongzhou Huang; Yingyu Wang; Weiguo Wan; Hejian Zou; Bin Wang; Xiaoyan Qiu; Xue Yang

doi:10.1016/j.freeradbiomed.2024.05.013

Upregulation of GPX4 drives ferroptosis resistance in scleroderma skin fibroblasts

Free Radic Biol Med. 2024 May 11:221:23-30. doi: 10.1016/j.freeradbiomed.2024.05.013. Online ahead of print.

Authors

Fali Zhang¹, Yu Xiao², Zhongzhou Huang², Yingyu Wang², Weiguo Wan², Hejian Zou², Bin Wang¹, Xiaoyan Qiu³, Xue Yang⁴

Affiliations

¹ Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China.
² Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, 200040, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, 200040, China.
³ Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China. Electronic address: xyqiu@fudan.edu.cn.
⁴ Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, 200040, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, 200040, China. Electronic address: yangxue21@yeah.net.

PMID: 38740100
DOI: 10.1016/j.freeradbiomed.2024.05.013

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.

Keywords: ); Erastin; Erastin (PubChem CID: 11214940); Fibroblasts; GPX4; RSL3; RSL3 (PubChem CID: 1750826; Systemic sclerosis.