Multifaceted Roles for Persulfide Species in Redox Chemical Biology

Reactive sulfur species (RSS) are increasingly recognized as important bioactive agents across phyla. Application of newly developed chemical tools, detection methods and multi-omics techniques has uncovered novel and specific roles of endogenous RSS and revealed that a number of biological actions previously attributed to reactive oxygen (ROS) or nitrogen (RNS) species can also be mediated by RSS. This Perspective describes the versatile chemical biology of RSS with focus on persulfide formation on cysteine residues. We cover their pro- and antioxidant capacities, involvement in redox signaling and metabolic pathways, stress responses, as well as in the pathophysiology of major disease groups, such as cardiovascular and neurodegenerative ailments and cancer. We also provide a critical discussion of available detection methods and potential pharmacological and genetic approaches to adjusting persulfide levels. We cover current knowledge and its limitations, along with practical recommendations for advancing persulfide-based therapeutic interventions.