{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T07:42:19Z","timestamp":1791013339018,"version":"4.1.0"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T00:00:00Z","timestamp":1646265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81974021 82170304 81930012 81974012 82170232 82070386"],"award-info":[{"award-number":["81974021 82170304 81930012 81974012 82170232 82070386"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","award":["20ZR1435500"],"award-info":[{"award-number":["20ZR1435500"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>As one of the cornerstones of clinical cardiovascular disease treatment, statins have an extensive range of applications. However, statins commonly used have side reactions, especially muscle-related symptoms (SAMS), such as muscle weakness, pain, cramps, and severe condition of rhabdomyolysis. This undesirable muscular effect is one of the chief reasons for statin non-adherence and\/or discontinuation, contributing to adverse cardiovascular outcomes. Moreover, the underlying mechanism of muscle cell damage is still unclear. Here, we discovered that ferroptosis, a programmed iron-dependent cell death, serves as a mechanism in statin-induced myopathy. Among four candidates including atorvastatin, lovastatin, rosuvastatin, and pravastatin, only atorvastatin could lead to ferroptosis in human cardiomyocytes (HCM) and murine skeletal muscle cells (C2C12), instead of human umbilical vein endothelial cell (HUVEC). Atorvastatin inhibits HCM and C2C12 cell viability in a dose-dependent manner, accompanying with significant augmentation in intracellular iron ions, reactive oxygen species (ROS), and lipid peroxidation. A noteworthy investigation found that those alterations particularly occurred in mitochondria and resulted in mitochondrial dysfunction. Biomarkers of myocardial injury increase significantly during atorvastatin intervention. However, all of the aforementioned enhancement could be restrained by ferroptosis inhibitors. Mechanistically, GSH depletion and the decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPx4), and xCT cystine\u2013glutamate antiporter (the main component is SLC7A11) are involved in atorvastatin-induced muscular cell ferroptosis and damage. The downregulation of GPx4 in mitochondria-mediated ferroptosis signaling may be the core of it. In conclusion, our findings explore an innovative underlying pathophysiological mechanism of atorvastatin-induced myopathy and highlight that targeting ferroptosis serves as a protective strategy for clinical application.<\/jats:p>","DOI":"10.3389\/fcell.2022.806081","type":"journal-article","created":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T01:41:05Z","timestamp":1646271665000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":87,"title":["Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT\/GPx4 Axis"],"prefix":"10.3389","volume":"10","author":[{"given":"Qi","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyang","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengjun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex F.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/s41419-021-03669-w","article-title":"Simvastatin Accelerated Motoneurons Death in SOD1G93A Mice through Inhibiting Rab7-Mediated Maturation of Late Autophagic Vacuoles","volume":"12","author":"Bai","year":"2021","journal-title":"Cell Death Dis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.mayocp.2014.08.021","article-title":"Effects of Coenzyme Q10 on Statin-Induced Myopathy","volume":"90","author":"Banach","year":"2015","journal-title":"Mayo Clinic Proc."},{"key":"B3","doi-asserted-by":"publisher","first-page":"205","DOI":"10.3390\/nu11010205","article-title":"The Effects of Quercetin Supplementation on Eccentric Exercise-Induced Muscle Damage","volume":"11","author":"Bazzucchi","year":"2019","journal-title":"Nutrients"},{"key":"B4","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.jacbts.2017.01.009","article-title":"Pravastatin but Not Simvastatin Improves Survival and Neurofunctional Outcome after Cardiac Arrest and Cardiopulmonary Resuscitation","volume":"2","author":"Bergt","year":"2017","journal-title":"JACC: Basic Translational Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1038\/s41586-019-1705-2","article-title":"The CoQ Oxidoreductase FSP1 Acts Parallel to GPX4 to Inhibit Ferroptosis","volume":"575","author":"Bersuker","year":"2019","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1007\/s00204-014-1378-4","article-title":"Simvastatin Induces Mitochondrial Dysfunction and Increased Atrogin-1 Expression in H9c2 Cardiomyocytes and Mice In Vivo","volume":"90","author":"Bonifacio","year":"2016","journal-title":"Arch. 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