心脏毒性
基因敲除
索拉非尼
ATF4
癌症研究
未折叠蛋白反应
综合应力响应
药理学
细胞凋亡
氧化应激
化学
医学
细胞生物学
生物
内科学
生物化学
毒性
肝细胞癌
信使核糖核酸
基因
翻译(生物学)
作者
Hui Jiang,Cong Wang,An Zhang,Yufeng Li,Jianping Li,Zhan Li,Xin Yang,Yinglong Hou
标识
DOI:10.1016/j.biopha.2022.113280
摘要
Sorafenib (SOR) is an effective chemotherapy drug for hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma. However, a long-standing clinical issue associated with SOR use is an increased risk of cardiotoxicity, but the underlying mechanisms remain obscure. Here we report that ferroptosis of cardiomyocytes is responsible for SOR-induced cardiotoxicity. The specific ferroptosis inhibitor ferrostatin-1 and deferoxamine mesylate, an iron chelator, significantly alleviate SOR-induced cardiac damage. RNA-sequencing revealed that endoplasmic reticulum (ER) stress and the unfolded protein response were predominately activated, which might be attributed to the lipid reactive oxygen species-mediated perturbation of the ER. Activating transcription factor 4 (ATF4) is one of the most significantly up-regulated genes, knockdown of ATF4 exacerbates cardiomyocyte ferroptosis induced by SOR, while overexpression of ATF4 promotes cell survival. Mice with AAV-mediated ATF4 knockdown exhibit lipid peroxidation and more severe cardiomyopathy. Further experiments demonstrated that ATF4 exerts its protective role by elevating SLC7A11 expression, a transport subunit of system Xc-, which promotes cystine uptake and glutathione biosynthesis. The cardioprotective effect of ATF4 was diminished by SLC7A11 knockdown in cardiomyocytes subjected to SOR treatment. Taken together, these findings show that ferroptosis of cardiomyocytes is an important cause of SOR-related cardiotoxicity. ATF4 acts as a key regulator to promote cardiomyocytes survival by up-regulation of SLC7A11 and suppression of ferroptosis.
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