Closing the H2S/NO Signaling Loop: Nitric Oxide Regeneration by a Synthetic Zn2+ Persulfide via Transnitrosation and Nitrite Reduction

Cross-talk between reactive sulfur species (RSS) and reactive nitrogen species (RNS) is increasingly recognized as a central feature of biological redox signaling, yet the molecular basis for which persulfides (RSS – ) engage with nitrosative intermediates remains poorly defined. Motivated by the emerging roles of Zn 2+ persulfides in NO-mediated signaling, we report the synthesis, characterization, and reactivity of a well-defined Zn2+ alkyl persulfide complex, [Zn 2+ (Mes 3 TPA)(SStBu)] + toward various nitrosating reagents. This Zn 2+ persulfide is inert toward NO• and tert-butyl nitrite (tBuONO) but reacts rapidly with Snitrosothiols (RSNOs) and NO + through formation of a transient S-nitrosopersulfide (tBuSSNO) intermediate. Subsequent homolytic S–N cleavage releases NO • and a perthiyl radical (tBuSS • ), which dimerizes to form the corresponding organic tetrasulfide, tBuSSSStBu. Although free nitrite (NO 2 – ) is unreactive toward the Zn-SSR complex, activation with either a Brønsted or Lewis acid enables efficient nitrite reduction to release NO • . Taken together, these results establish a molecular framework for Zn 2+ –persulfide mediated NO • regeneration and demonstrate how persulfidation can transform redox-inert Zn 2+ centers into dynamic redox sites that integrate RSS and RNS signaling.