Department of Cardiovascular Medicine and.
Department of Experimental and Clinical Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
JCI Insight. 2020 May 7;5(9):132747. doi: 10.1172/jci.insight.132747.
Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin-induced cardiomyopathy (DIC). This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. Here, we show that DOX downregulated glutathione peroxidase 4 (GPx4) and induced excessive lipid peroxidation through DOX-Fe2+ complex in mitochondria, leading to mitochondria-dependent ferroptosis; we also show that mitochondria-dependent ferroptosis is a major cause of DOX cardiotoxicity. In DIC mice, the left ventricular ejection fraction was significantly impaired, and fibrosis and TUNEL+ cells were induced at day 14. Additionally, GPx4, an endogenous regulator of ferroptosis, was downregulated, accompanied by the accumulation of lipid peroxides, especially in mitochondria. These cardiac impairments were ameliorated in GPx4 Tg mice and exacerbated in GPx4 heterodeletion mice. In cultured cardiomyocytes, GPx4 overexpression or iron chelation targeting Fe2+ in mitochondria prevented DOX-induced ferroptosis, demonstrating that DOX triggered ferroptosis in mitochondria. Furthermore, concomitant inhibition of ferroptosis and apoptosis with ferrostatin-1 and zVAD-FMK fully prevented DOX-induced cardiomyocyte death. Our findings suggest that mitochondria-dependent ferroptosis plays a key role in progression of DIC and that ferroptosis is the major form of regulated cell death in DOX cardiotoxicity.
多柔比星（DOX）是一种化疗药物，可引起一种称为多柔比星诱导性心肌病（DIC）的心脏毒性。这种心脏毒性通常会限制恶性肿瘤的化疗，并与预后不良相关。然而，这种心脏毒性的分子机制尚未完全阐明。在这里，我们表明 DOX 通过线粒体中的 DOX-Fe2+复合物下调谷胱甘肽过氧化物酶 4（GPx4）并诱导过度的脂质过氧化，导致线粒体依赖性铁死亡；我们还表明，线粒体依赖性铁死亡是 DOX 心脏毒性的主要原因。在 DIC 小鼠中，左心室射血分数明显受损，第 14 天诱导纤维化和 TUNEL+细胞。此外，GPx4，一种铁死亡的内源性调节剂，下调，伴随着脂质过氧化物的积累，特别是在线粒体中。这些心脏损伤在 GPx4 Tg 小鼠中得到改善，在 GPx4 杂合缺失小鼠中恶化。在培养的心肌细胞中，GPx4 的过表达或针对线粒体中 Fe2+的铁螯合作用可防止 DOX 诱导的铁死亡，表明 DOX 触发了线粒体中的铁死亡。此外，用 ferrostatin-1 和 zVAD-FMK 同时抑制铁死亡和凋亡可完全防止 DOX 诱导的心肌细胞死亡。我们的研究结果表明，线粒体依赖性铁死亡在 DIC 的进展中起关键作用，并且铁死亡是 DOX 心脏毒性中主要的细胞死亡形式。
