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

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Ferroptosis, a regulated cell death, is driven by iron-dependent redox imbalance and lipid reactive oxygen species (ROS) accumulation.
• Cellular defense mechanisms exist to prevent ferroptosis, but novel inhibitors are sought for therapeutic applications.

Purpose of the Study:

• To identify novel inhibitors of ferroptosis from bioactive compounds.
• To elucidate the mechanism of action for ferroptosis inhibition by identified compounds.

Main Methods:

• Screening of over 4,000 bioactive compounds to identify ferroptosis inhibitors.
• Investigating the molecular mechanism of inhibition using biochemical assays and cell-based models.
• Evaluating the efficacy of the identified compound in mouse models of acute liver injury and ischemia/reperfusion heart injury.

Main Results:

• Tanshinone from Salvia miltiorrhiza (Danshen) demonstrated potent ferroptosis inhibitory activity.
• Tanshinone acts as a coenzyme for NAD(P)H:quinone oxidoreductase 1 (NQO1), enhancing its detoxification of lipid peroxyl radicals.
• This NQO1-tanshinone interaction inhibits ferroptosis in vitro and in vivo, showing protective effects in liver and heart injury models.

Conclusions:

• Tanshinone represents a novel ferroptosis inhibitor through a NQO1-dependent mechanism.
• This study reveals a gain-of-function for NQO1 induced by tanshinone, a new pathway for ferroptosis inhibition.
• The findings support the clinical relevance of tanshinone in mitigating ferroptosis-associated organ damage.