Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi, 710072, China.
Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
Free Radic Biol Med. 2024 Oct;223:224-236. doi: 10.1016/j.freeradbiomed.2024.08.001. Epub 2024 Aug 6.
Doxorubicin (DOX) is an anthracycline medication that is commonly used to treat solid tumors. However, DOX has limited clinical efficacy due to known cardiotoxicity. Ferroptosis is involved in DOX-induced cardiotoxicity (DIC). Although mitsugumin-53 (MG53) has cardioprotective effects and is expected to attenuate myocardial ischemic injury, its ability to inhibit DOX-induced ferroptosis has not been extensively studied. This research aims to investigate the pathophysiological impact of MG53 on DOX induced ferroptosis. Here, MG53 levels were evaluated in relation to the extent of ferroptosis by establishing in vivo and in vitro DIC mouse models. Additionally, myocardial specific MG53 overexpressing mice were used to study the effect of MG53 on cardiac function in DIC mice. The study found that the MG53 expression decreased in DOX treated mouse hearts or cardiomyocytes. However, MG53-overexpressing improved cardiac function in the DIC model and effectively reduced myocardial ferroptosis by increasing solute carrier family 7 member 11 (SLC7A11) and Glutathione peroxidase 4 (GPX4) levels, which were decreased by DOX. Mechanistically, MG53 binds to tumor suppressor 53 (p53) to regulate its ubiquitination and degradation. Ferroptosis induced by DOX was prevented by either MG53 overexpression or p53 knockdown in cardiomyocytes. The modulation of the p53/SLC7A11/GPX4 pathway by overexpression of MG53 can alleviate DOX induced ferroptosis. The study indicates that MG53 can provide protection against DIC by increasing p53 ubiquitination. These results highlight the previously unidentified role of MG53 in inhibiting ferroptosis to prevent DIC.
阿霉素（DOX）是一种蒽环类药物，常用于治疗实体瘤。然而，由于已知的心脏毒性，DOX 的临床疗效有限。铁死亡参与了 DOX 诱导的心脏毒性（DIC）。虽然肌球蛋白结合蛋白 53（MG53）具有心脏保护作用，并有望减轻心肌缺血性损伤，但它抑制 DOX 诱导的铁死亡的能力尚未得到广泛研究。本研究旨在探讨 MG53 对 DOX 诱导的铁死亡的病理生理影响。在这里，通过建立体内和体外 DIC 小鼠模型，评估了 MG53 水平与铁死亡程度的关系。此外，还使用心肌特异性 MG53 过表达小鼠研究了 MG53 对 DIC 小鼠心脏功能的影响。研究发现，DOX 处理的小鼠心脏或心肌细胞中 MG53 表达降低。然而，MG53 过表达改善了 DIC 模型中的心脏功能，并通过增加溶质载体家族 7 成员 11（SLC7A11）和谷胱甘肽过氧化物酶 4（GPX4）水平有效减少了心肌铁死亡，这些水平在 DOX 处理后降低。从机制上讲，MG53 与肿瘤抑制因子 53（p53）结合，调节其泛素化和降解。在心肌细胞中，MG53 过表达或 p53 敲低均可预防 DOX 诱导的铁死亡。MG53 过表达对 p53/SLC7A11/GPX4 通路的调节可以减轻 DOX 诱导的铁死亡。该研究表明，MG53 通过增加 p53 泛素化来提供对 DIC 的保护。这些结果突出了 MG53 抑制铁死亡以预防 DIC 的先前未知作用。
