Hydropersulfides (RSSH) play essential roles in cellular signaling and redox balance, yet their regulatory mechanisms remain elusive. While significant progress has been made in understanding their biosynthesis, little is known about how cells respond to dysregulated RSSH levels. Investigating these reactive species has been challenging due to their inherent instability. To address this issue, a series of arylsulfonothioates have been synthesized with various electron-donating and withdrawing substituents, designed to persulfidate biological thiols (RSH) and generate RSSH. These compounds provide a robust chemical tool for studying how cells respond to increased RSSH levels. Findings reveal that cardiac cells tightly regulate RSSH based on physiological conditions. Under normal conditions, excess RSSH is excreted via the cystine/glutamate antiporter to maintain redox homeostasis and prevent toxicity. However, under oxidative stress, cells retain RSSH, leveraging their cytoprotective properties. This study advances our understanding of RSSH homeostasis.
