2. Academic Validation
  3. 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

  • Life Sci Alliance. 2022 Nov 1;6(1):e202201667. doi: 10.26508/lsa.202201667.
Tian-Xiang Wang 1,  Kun-Long Duan 1,  Zi-Xuan Huang 1,  Zi-An Xue 1,  Jun-Yun Liang 1,  Yongjun Dang 2,  Ao Zhang 3,  Yue Xiong 4,  Chunyong Ding 5,  Kun-Liang Guan 6,  Hai-Xin Yuan 7 2
Affiliations

Affiliations

  • 1 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.
  • 2 Center for Novel Target and Therapeutic Intervention, Chongqing Medical University, Chongqing, China.
  • 3 Pharm-X Center, College of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Cullgen Inc., San Diego, CA, USA.
  • 5 Pharm-X Center, College of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China yuanhaixin@fudan.edu.cn chunding@sjtu.edu.cn.
  • 6 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
  • 7 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 yuanhaixin@fudan.edu.cn chunding@sjtu.edu.cn.
PMID: 36319062 DOI: 10.26508/lsa.202201667
Abstract

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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