Engineered Substrates for a Sulfurtransferase Enhance Endogenous Hydropersulfides and Inhibit Ferroptosis

ABSTRACT Cellular hydropersulfides (RS‐SH) derived from hydrogen sulfide (H 2 S) such as glutathione hydropersulfide (GS‐SH) are excellent hydrogen atom transfer agents, and quench radicals to protect cells from ferroptosis, a form of iron‐mediated cell death associated with an unchecked build‐up of lipid radicals. Here, using principles of enzyme‐inhibitor design, a series of new artificial substrates for the endogenous hydropersulfide‐generating enzyme, 3‐mercaptopyruvate sulfurtransferase (3‐MST) was developed. We find that the lead molecules generated GS‐SH, catalyzed by 3‐MST, permeated cells to enhance endogenous hydropersulfides, protected cells from ferroptosis, and reduced systemic inflammation in an animal model. Together, this calibrated approach to promote cell's own radical trapping antioxidants using its biosynthetic machinery to prevent ferroptosis has tremendous implications in redox biology and therapeutics.