Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, 200040, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, 200040, China.
Free Radic Biol Med. 2024 Aug 20;221:23-30. doi: 10.1016/j.freeradbiomed.2024.05.013. Epub 2024 May 11.
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.
系统性硬化症 (SSC) 纤维化的发病机制涉及皮肤成纤维细胞的快速增殖，而目前的抗纤维化治疗方法有限。本研究探讨了铁死亡与 SSC 皮肤成纤维细胞之间的关系。我们观察到，SSC 成纤维细胞中，依马替尼诱导的铁死亡受到抑制。RSL3，谷胱甘肽过氧化物酶 4 (GPX4) 的直接抑制剂，显著降低了成纤维细胞的活力，而 SSC 成纤维细胞中 GPX4 的上调有助于铁死亡抵抗。此外，我们证明转铁蛋白受体 1 (TfR1) 是铁在成纤维细胞中沉积的关键转运蛋白。综上所述，我们的研究结果强调了 GPX4 抑制可能通过 SSC 成纤维细胞增强铁死亡的敏感性，这表明铁代谢的特征与本研究中正常成纤维细胞不同。总之，这些结果表明，针对铁死亡可能是治疗 SSC 的一种治疗策略。
