Engineered Substrates for a Sulfurtransferase Enhance Endogenous Hydropersulfides and Inhibit Ferroptosis

Area of Science:

• Redox biology
• Biochemistry
• Pharmacology

Background:

• Cellular hydropersulfides (RS-SH), like glutathione hydropersulfide (GS-SH), are crucial antioxidants.
• These compounds neutralize free radicals and protect cells from ferroptosis, a form of iron-induced cell death.
• Ferroptosis is characterized by the accumulation of lipid radicals.

Purpose of the Study:

• To design novel artificial substrates for 3-mercaptopyruvate sulfurtransferase (3-MST).
• To enhance endogenous cellular hydropersulfide levels using enzyme-catalyzed reactions.
• To investigate the protective effects against ferroptosis and systemic inflammation.

Main Methods:

• Employed enzyme-inhibitor design principles to create new 3-MST substrates.
• Synthesized and tested lead molecules for their ability to generate GS-SH.
• Assessed cellular penetration, ferroptosis protection, and anti-inflammatory effects in an animal model.

Main Results:

• Developed lead molecules that effectively generate GS-SH catalyzed by 3-MST.
• Demonstrated that these molecules enhance endogenous hydropersulfides within cells.
• Showed protection against ferroptosis and a reduction in systemic inflammation in vivo.

Conclusions:

• A novel strategy was established to boost cellular radical-trapping antioxidants via endogenous biosynthetic pathways.
• This approach effectively prevents ferroptosis by enhancing cellular hydropersulfide levels.
• The findings hold significant implications for redox biology and the development of new therapeutics.