Hydropersulfide Donors: Mechanistic and Kinetic Insights With Biological and Potential Therapeutic Implications

Hydropersulfides (RSSH) are emerging reactive sulfur species with distinctive chemical properties. Compared with conventional thiols and disulfides, RSSH exhibit enhanced acidity, nucleophilicity, reducing capabilities, and electrophilicity, enabling unique redox and sulfur transfer activity under physiological conditions. Their intrinsic instability and high reactivity have limited direct mechanistic studies. Over the past decade, a range of small‐molecule RSSH donors have been developed to probe RSSH chemistry and biology. In this review, we survey different strategies for RSSH generation, including direct‐release donors and self‐immolative platforms, the latter of which exploit elimination cascades or cyclization‐triggered mechanisms to achieve controlled RSSH release. We discuss trigger‐specific activation, structure–activity relationships, and factors governing RSSH release kinetics. We also highlight emerging biological applications of RSSH donors, where studies have explored their potential to modulate oxidative and nitrosative stress, maintain cellular redox balance, and mitigate tissue injury in cardiac, hepatic, and neuronal models. These investigations underscore the utility of RSSH donors as chemical biology tools for interrogating redox signaling and as potential pharmacological agents for the treatment of myriad pathologies associated with disrupted redox homeostasis.