Protosappanin A Protects DOX‐Induced Myocardial Injury and Cardiac Dysfunction by Targeting ACSL4/FTH1 Axis‐Dependent Ferroptosis

• DOI: 10.1002/advs.202310227
• Publication Date: 2024-07-10T09:23:21Z
• Authors: 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
• Keywords: Cardiac Dysfunction

Abstract Doxorubicin (DOX) is an effective anticancer agent, but its clinical utility constrained by dose‐dependent cardiotoxicity, partly due to cardiomyocyte ferroptosis. However, the progress of developing cardioprotective medications counteract ferroptosis has encountered obstacles. Protosappanin A (PrA), anti‐inflammatory compound derived from hematoxylin, shows potential against DOX‐induced cardiomyopathy (DIC). Here, it reported that PrA alleviates myocardial damage and dysfunction reducing maintaining mitochondrial homeostasis. Subsequently, molecular target through proteome microarray, docking, dynamics simulation identified. Mechanistically, physically binds with ferroptosis‐related proteins acyl‐CoA synthetase long‐chain family member 4 (ACSL4) ferritin heavy chain 1 (FTH1), ultimately inhibiting ACSL4 phosphorylation subsequent phospholipid peroxidation, while also preventing FTH1 autophagic degradation release ferrous ions (Fe 2+ ) release. Given critical role in pathogenesis ischemia‐reperfusion (IR) injury, this further investigation posits can confer a protective effect IR‐induced cardiac Overall, novel pharmacological inhibitor unveiled targets uncover dual‐regulated mechanism for DIC, highlighting additional therapeutic options chemodrug‐induced cardiotoxicity ferroptosis‐triggered disorders.