Tanshinone functions as a coenzyme that confers gain of function of NQO1 to suppress ferroptosis

• Published in: Life science alliance Vol. 6; no. 1; p. e202201667
• Main Authors: Wang, Tian-Xiang, Duan, Kun-Long, Huang, Zi-Xuan, Xue, Zi-An, Liang, Jun-Yun, Dang, Yongjun, Zhang, Ao, Xiong, Yue, Ding, Chunyong, Guan, Kun-Liang, Yuan, Hai-Xin
• Format: Journal Article
• Language: English
• Published: United States Life Science Alliance LLC 01.01.2023
• Subjects: Animals; Coenzymes - metabolism; Ferroptosis; Gain of Function Mutation; Lipids; Mice; Reactive Oxygen Species - metabolism; Salvia miltiorrhiza - metabolism
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202201667

Ferroptosis is triggered by the breakdown of cellular iron-dependent redox homeostasis and the abnormal accumulation of lipid ROS. Cells have evolved defense mechanisms to prevent lipid ROS accumulation and ferroptosis. Using a library of more than 4,000 bioactive compounds, we show that tanshinone from (Danshen) has very potent inhibitory activity against ferroptosis. Mechanistically, we found that tanshinone functions as a coenzyme for NAD(P)H:quinone oxidoreductase 1 (NQO1), which detoxifies lipid peroxyl radicals and inhibits ferroptosis both in vitro and in vivo. Although NQO1 is recognized as an oxidative stress response gene, it does not appear to have a direct role in ferroptosis inhibition in the absence of tanshinone. Here, we demonstrate a gain of function of NQO1 induced by tanshinone, which is a novel mechanism for ferroptosis inhibition. Using mouse models of acute liver injury and ischemia/reperfusion heart injury, we observed that tanshinone displays protective effects in both the liver and the heart in a manner dependent on NQO1. Our results link the clinical use of tanshinone to its activity in ferroptosis inhibition.