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. Print 2023 Jan.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coenzymes / metabolism
  • Ferroptosis*
  • Gain of Function Mutation
  • Lipids
  • Mice
  • Reactive Oxygen Species / metabolism
  • Salvia miltiorrhiza* / metabolism

Substances

  • Coenzymes
  • Lipids
  • Reactive Oxygen Species
  • tanshinone
  • Nqo1 protein, mouse