The Fifth People's Hospital of Shanghai, The Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences and the School of Pharmacy, Fudan University, Shanghai, China.
Center for Novel Target and Therapeutic Intervention, Chongqing Medical University, Chongqing, China.
Life Sci Alliance. 2022 Nov 1;6(1). doi: 10.26508/lsa.202201667. Print 2023 Jan.
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.
铁死亡是由细胞内铁依赖的氧化还原稳态的破坏和脂质 ROS 的异常积累引发的。细胞已经进化出防御机制来防止脂质 ROS 积累和铁死亡。我们使用了一个包含超过 4000 种生物活性化合物的文库，表明丹参中的丹参酮对铁死亡具有很强的抑制活性。在机制上，我们发现丹参酮作为 NAD(P)H:醌氧化还原酶 1 (NQO1)的辅酶，在体外和体内都能解毒脂质过氧自由基并抑制铁死亡。尽管 NQO1 被认为是一种氧化应激反应基因，但在没有丹参酮的情况下，它似乎并没有直接参与铁死亡抑制。在这里，我们证明了丹参酮诱导的 NQO1 的功能获得，这是一种抑制铁死亡的新机制。使用急性肝损伤和缺血/再灌注心脏损伤的小鼠模型，我们观察到丹参酮在肝脏和心脏中均表现出依赖于 NQO1 的保护作用。我们的结果将丹参酮的临床应用与其在抑制铁死亡中的活性联系起来。
