Simvastatin-Induced Ferroptosis in Orbital Fibroblasts in Graves' Ophthalmopathy

Overview

Journal Invest Ophthalmol Vis Sci

Date 2025 Jan 24

PMID 39854011

Authors

Lujue Wang

Yuan Li

Tongxin Niu

Jing Deng

Yuxian Shi

Yating Liu

Boding Tong

Xin Qi

Dan Cao

Yongguang Tao

Yunping Li

Affiliations

Soon will be listed here.

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.

References

Wei Y, Liao S, Wang S, Wang C, Yang C . Simvastatin and ROCK Inhibitor Y-27632 Inhibit Myofibroblast Differentiation of Graves' Ophthalmopathy-Derived Orbital Fibroblasts RhoA-Mediated ERK and p38 Signaling Pathways. Front Endocrinol (Lausanne). 2021; 11:607968. PMC: 7883643. DOI: 10.3389/fendo.2020.607968. View

Shu X, Wu J, Zhang T, Ma X, Du Z, Xu J . Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes Ferroptosis-Related Senescence in Adipose Tissue. Nutrients. 2022; 14(20). PMC: 9607568. DOI: 10.3390/nu14204365. View

Yuan H, Li X, Zhang X, Kang R, Tang D . Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016; 478(3):1338-43. DOI: 10.1016/j.bbrc.2016.08.124. View

Wei Y, Liao S, Wang C, Wang S, Tang W, Yang C . Simvastatin Inhibits CYR61 Expression in Orbital Fibroblasts in Graves' Ophthalmopathy through the Regulation of FoxO3a Signaling. Mediators Inflamm. 2021; 2021:8888913. PMC: 7843182. DOI: 10.1155/2021/8888913. View

Nilsson A, Tsoumani K, Planck T . Statins Decrease the Risk of Orbitopathy in Newly Diagnosed Patients with Graves Disease. J Clin Endocrinol Metab. 2021; 106(5):1325-1332. DOI: 10.1210/clinem/dgab070. View

Yao X, Xie R, Cao Y, Tang J, Men Y, Peng H . Simvastatin induced ferroptosis for triple-negative breast cancer therapy. J Nanobiotechnology. 2021; 19(1):311. PMC: 8502296. DOI: 10.1186/s12951-021-01058-1. View

Lanzolla G, Vannucchi G, Ionni I, Campi I, Sileo F, Lazzaroni E . Cholesterol Serum Levels and Use of Statins in Graves' Orbitopathy: A New Starting Point for the Therapy. Front Endocrinol (Lausanne). 2020; 10:933. PMC: 6987298. DOI: 10.3389/fendo.2019.00933. View

Marino M, Lanzolla G, Marcocci C . Statins: A New Hope on the Horizon of Graves Orbitopathy?. J Clin Endocrinol Metab. 2021; 106(7):e2819-e2821. DOI: 10.1210/clinem/dgab184. View

Chen P, Wang D, Xiao T, Gu W, Yang H, Yang M . ACSL4 promotes ferroptosis and M1 macrophage polarization to regulate the tumorigenesis of nasopharyngeal carcinoma. Int Immunopharmacol. 2023; 122:110629. DOI: 10.1016/j.intimp.2023.110629. View

10.

Ding K, Liu C, Li L, Yang M, Jiang N, Luo S . Acyl-CoA synthase ACSL4: an essential target in ferroptosis and fatty acid metabolism. Chin Med J (Engl). 2023; 136(21):2521-2537. PMC: 10617883. DOI: 10.1097/CM9.0000000000002533. View

11.

Lee J, Kim W, Bae K, Lee S, Lee E . Lipid Metabolism and Ferroptosis. Biology (Basel). 2021; 10(3). PMC: 8000263. DOI: 10.3390/biology10030184. View

12.

Bartalena L, Tanda M . Current concepts regarding Graves' orbitopathy. J Intern Med. 2022; 292(5):692-716. PMC: 9796560. DOI: 10.1111/joim.13524. View

13.

Liu J, Pan Z, Tong B, Wang C, Yang J, Zou J . Artesunate protects against ocular fibrosis by suppressing fibroblast activation and inducing mitochondria-dependent ferroptosis. FASEB J. 2023; 37(6):e22954. DOI: 10.1096/fj.202201867R. View

14.

Bartalena L, Piantanida E, Gallo D, Lai A, Tanda M . Epidemiology, Natural History, Risk Factors, and Prevention of Graves' Orbitopathy. Front Endocrinol (Lausanne). 2020; 11:615993. PMC: 7734282. DOI: 10.3389/fendo.2020.615993. View

15.

Doll S, Proneth B, Tyurina Y, Panzilius E, Kobayashi S, Ingold I . ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2016; 13(1):91-98. PMC: 5610546. DOI: 10.1038/nchembio.2239. View

16.

Shahida B, Johnson P, Jain R, Brorson H, Asman P, Lantz M . Simvastatin downregulates adipogenesis in 3T3-L1 preadipocytes and orbital fibroblasts from Graves' ophthalmopathy patients. Endocr Connect. 2019; 8(9):1230-1239. PMC: 6733370. DOI: 10.1530/EC-19-0319. View

17.

Cheng J, Fan Y, Liu B, Zhou H, Wang J, Chen Q . ACSL4 suppresses glioma cells proliferation via activating ferroptosis. Oncol Rep. 2019; 43(1):147-158. PMC: 6912066. DOI: 10.3892/or.2019.7419. View

18.

Ma R, Gan L, Guo J, Peng Z, Wu J, Harrison A . Insights Into Ferroptosis: Targeting Glycolysis to Treat Graves' Orbitopathy. J Clin Endocrinol Metab. 2022; 107(7):1994-2003. DOI: 10.1210/clinem/dgac163. View

19.

Lanzolla G, Sabini E, Leo M, Menconi F, Rocchi R, Sframeli A . Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial. Lancet Diabetes Endocrinol. 2021; 9(11):733-742. DOI: 10.1016/S2213-8587(21)00238-2. View

20.

Reynolds A, Del Monte M, Archer S . The effect of oral statin therapy on strabismus in patients with thyroid eye disease. J AAPOS. 2018; 22(5):340-343. DOI: 10.1016/j.jaapos.2018.04.009. View