Tanshinone functions as a coenzyme that confers gain of function of NQO1 to suppress ferroptosis.
Tanshinone functions as a coenzyme that confers gain of function of NQO1 to suppress ferroptosis.
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丹参酮作为辅酶，赋予 NQO1 抑制铁死亡的功能
DOI：
10.26508/lsa.202201667
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发表时间：
2023-01
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
NQO 1在体内外均能催化丹参酮还原，消除脂质过氧自由基，抑制铁中毒，为丹参酮的心脏保护等治疗作用提供了分子机制。铁凋亡是由细胞铁依赖性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积累和铁凋亡。使用超过4,000个生物活性化合物的库，我们表明丹参（丹参）中的丹参酮对铁凋亡具有非常有效的抑制活性。机制上，我们发现丹参酮作为辅酶NAD（P）H：醌氧化还原酶1（NQO 1），解毒脂质过氧自由基和抑制铁凋亡在体外和体内。虽然NQO 1被认为是一种氧化应激反应基因，但在丹参酮不存在的情况下，它似乎在铁凋亡抑制中没有直接作用。在这里，我们证明了丹参酮诱导的NQO 1功能的增益，这是一种新的抑制铁凋亡的机制。使用小鼠急性肝损伤和缺血/再灌注心脏损伤模型，我们观察到丹参酮显示在肝脏和心脏的保护作用的方式依赖于NQO 1。我们的研究结果将丹参酮的临床应用与其抑制铁凋亡的活性联系起来。
NQO1 catalyzes the reduction of tanshinones to detoxify lipid peroxyl radicals and inhibit ferroptosis both in vitro and in vivo, providing a molecular mechanism for the therapeutic effects of tanshinones, such as cardiac protection. 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 Salvia miltiorrhiza (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.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
19
作者：
Yang WS;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
64.8
作者：
Mishima, Eikan;Ito, Junya;Wu, Zijun;Nakamura, Toshitaka;Wahida, Adam;Doll, Sebastian;Tonnus, Wulf;Nepachalovich, Palina;Eggenhofer, Elke;Aldrovandi, Maceler;Henkelmann, Bernhard;Yamada, Ken-Ichi;Wanninger, Jonas;Zilka, Omkar;Sato, Emiko;Feederle, Regina;Hass, Daniela;Maida, Adriano;Mourao, Andre Santos Dias;Linkermann, Andreas;Geissler, Edward K.;Nakagawa, Kiyotaka;Abe, Takaaki;Fedorova, Maria;Proneth, Bettina;Pratt, Derek A.;Conrad, Marcus
通讯作者：
Conrad, Marcus
影响因子：
3.9
作者：
De Cabo, R;Cabello, R;Navas, P
通讯作者：
Navas, P
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M