Significance: Hydropersulfides (RSSH) are ubiquitous in prokaryotes, eukaryotic cells, and mammalian tissues. The unique chemical properties and prevalent nature of these species suggest a crucial role of RSSH in cell regulatory processes, yet little is known about their physiological functions. Recent Advances: Examining the biological roles of RSSH species is challenging because of their inherent instability. In recent years, researchers have developed a number of small-molecule donors that efficiently release RSSH in response to various stimuli, including pH, thiols, reactive oxygen species, enzymes, and light. These RSSH donors have provided researchers with chemical tools to uncover the potential function and role of RSSH as physiological signaling and/or protecting agents. Critical Issues: Because RSSH, hydrogen sulfide (H2S), and higher order polysulfides are related to each other and can be present simultaneously in biological systems, distinguishing among the activities due to each of these species is difficult. Discerning this activity is critical to elucidate the chemical biology and physiology of RSSH. Moreover, although RSSH donors have been shown to confer cytoprotection against oxidative and electrophilic stress, their biological targets remain to be elucidated. Future Directions: The development of RSSH donors with optimal drug-like properties and selectivity toward specific tissues/pathologies represents a promising approach. Further investigation of releasing efficiencies in vivo and a clear understanding of RSSH biological responses remain targets for future investigation. Antioxid. Redox Signal. 36, 309-326.
Keywords: antioxidant; cytoprotective agent; hydropersulfide; hydropersulfide donor; oxidative stress; persulfidation.