Simvastatin-Induced Ferroptosis in Orbital Fibroblasts in Graves' Ophthalmopathy.

Abstract

Purpose: Graves' ophthalmopathy (GO), the most common extrathyroidal manifestation of Graves' disease, is disabling and disfiguring. Recent studies have shown that statins have a protective effect on individuals with GO. Statins were reported to trigger ferroptosis in some disorders, but little is known about whether statins protect against GO via ferroptosis. The aim of this study was to explore whether ferroptosis is involved in the protective effect of simvastatin on GO.

Methods: GO-OFs, which are orbital fibroblasts (OFs) derived from individuals with GO, were analyzed for lipogenesis by RT-qPCR and Red Oil O staining posttreatment with simvastatin. CCK-8 assays, flow cytometric analysis, and transmission electron microscopy (TEM) were used to compare the sensitivity of GO-OFs and control-OFs to erastin-induced ferroptosis. The ferroptosis levels in the GO-OFs were evaluated by measuring cell viability, reactive oxygen species (ROS) levels, and lipid peroxidation levels and performing TEM analysis after treatment with simvastatin and Fer-1.

Results: The GO-OFs were resistant to erastin-induced ferroptosis. The viability and lipogenesis of the GO-OFs were significantly decreased, while the levels of ROS, lipid peroxidation, and the ferroptosis marker ACLS4 were increased upon treatment with simvastatin.

Conclusions: Our study indicated that ferroptosis plays an important role in the pathogenesis of GO and that simvastatin may induce ferroptosis, suggesting that this drug could serve as a novel therapeutic agent for GO.