Protosappanin A 通过靶向 ACSL4/FTH1 轴依赖性铁死亡来保护 DOX 引起的心肌损伤和心脏功能障碍。
Protosappanin A Protects DOX-Induced Myocardial Injury and Cardiac Dysfunction by Targeting ACSL4/FTH1 Axis-Dependent Ferroptosis.
发表日期：2024 Jul 10
作者：
Jingxuan Cui, Yujia Chen, Qiannan Yang, Peng Zhao, Mian Yang, Xiaoqi Wang, Ge Mang, Xiangyu Yan, Di Wang, Zhonghua Tong, Penghe Wang, Yingjin Kong, Naixin Wang, Dongni Wang, Nana Dong, Mingyang Liu, Mingyan E, Maomao Zhang, Bo Yu
来源：
MOLECULAR & CELLULAR PROTEOMICS
摘要：
阿霉素（DOX）是一种有效的抗癌药物，但其临床应用受到剂量依赖性心脏毒性的限制，部分原因是心肌细胞铁死亡。然而，开发抗铁死亡的心脏保护药物的进展遇到了障碍。原苏木素 A (PrA) 是一种源自苏木精的抗炎化合物，具有对抗 DOX 诱导的心肌病 (DIC) 的潜力。据报道，PrA 通过减少 DOX 诱导的铁死亡和维持线粒体稳态来减轻心肌损伤和功能障碍。随后，通过蛋白质组微阵列、分子对接和动力学模拟确定了PrA的分子靶点。从机制上讲，PrA 与铁死亡相关蛋白酰基辅酶 A 合成酶长链家族成员 4 (ACSL4) 和铁蛋白重链 1 (FTH1) 物理结合，最终抑制 ACSL4 磷酸化和随后的磷脂过氧化，同时还防止 FTH1 自噬降解和随后释放亚铁离子（Fe2）的释放。鉴于铁死亡在缺血再灌注 (IR) 损伤发病机制中的关键作用，这项进一步的研究认为 PrA 可以通过抑制铁死亡来对 IR 诱导的心脏损伤发挥保护作用。总体而言，一种新型药物抑制剂的出现，以铁死亡为目标，并揭示了 DIC 中心肌细胞铁死亡的双重调节机制，突出了化学药物引起的心脏毒性和铁死亡触发疾病的其他治疗选择。© 2024 作者。 《Advanced Science》由 Wiley‐VCH GmbH 出版。
Doxorubicin (DOX) is an effective anticancer agent, but its clinical utility is constrained by dose-dependent cardiotoxicity, partly due to cardiomyocyte ferroptosis. However, the progress of developing cardioprotective medications to counteract ferroptosis has encountered obstacles. Protosappanin A (PrA), an anti-inflammatory compound derived from hematoxylin, shows potential against DOX-induced cardiomyopathy (DIC). Here, it is reported that PrA alleviates myocardial damage and dysfunction by reducing DOX-induced ferroptosis and maintaining mitochondrial homeostasis. Subsequently, the molecular target of PrA through proteome microarray, molecular docking, and dynamics simulation is identified. Mechanistically, PrA physically binds with ferroptosis-related proteins acyl-CoA synthetase long-chain family member 4 (ACSL4) and ferritin heavy chain 1 (FTH1), ultimately inhibiting ACSL4 phosphorylation and subsequent phospholipid peroxidation, while also preventing FTH1 autophagic degradation and subsequent release of ferrous ions (Fe2+) release. Given the critical role of ferroptosis in the pathogenesis of ischemia-reperfusion (IR) injury, this further investigation posits that PrA can confer a protective effect against IR-induced cardiac damage by inhibiting ferroptosis. Overall, a novel pharmacological inhibitor is unveiled that targets ferroptosis and uncover a dual-regulated mechanism for cardiomyocyte ferroptosis in DIC, highlighting additional therapeutic options for chemodrug-induced cardiotoxicity and ferroptosis-triggered disorders.© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.