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1. Self-Reporting H2S Donors: Integrating H2S Release with Real-Time Fluorescence Detection

   https://doi.org/10.3390/chemistry7040116  

   Zhu, Changlei; Lukesh, John C (August 2025, Chemistry)

   Hydrogen sulfide (H2S), once regarded solely as a highly toxic gas, is now recognized as a crucial signaling molecule in plants, bacteria, and mammals. In humans, H2S signaling plays a role in numerous physiological and pathological processes, including vasodilation, neuromodulation, and cytoprotection. To exploit its biological functions and therapeutic potential, a wide range of H2S-releasing compounds, known as H2S donors, have been developed. These donors are designed to release H2S under physiological conditions in a controlled manner. Among them, self-reporting H2S donors are seen as a particularly innovative class, combining therapeutic delivery with real-time fluorescence-based detection. This dual functionality enables spatiotemporal monitoring of H2S release in biological environments, eliminating the need for additional sensors or probes that could disrupt cellular homeostasis. This review summarizes recent advancements in self-reporting H2S donor systems, organizing them based on their activation triggers, such as specific bioanalytes, enzymes, or external stimuli like light. The discussion covers their design strategies, performance in biological applications, and therapeutic potential. Key challenges are also highlighted, including the need for precise control of H2S release kinetics, accurate signal quantification, and improved biocompatibility. With continued refinement, self-reporting H2S donors offer great promise for creating multifunctional platforms that seamlessly integrate diagnostic imaging with therapeutic H2S delivery. 

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2. Recent Development of the Molecular and Cellular Mechanisms of Hydrogen Sulfide Gasotransmitter

   https://doi.org/10.3390/antiox11091788  

   Liu, Jianyun; Mesfin, Fikir M.; Hunter, Chelsea E.; Olson, Kenneth R.; Shelley, W. Christopher; Brokaw, John P.; Manohar, Krishna; Markel, Troy A. (September 2022, Antioxidants)

   Hydrogen sulfide has been recently identified as the third biological gasotransmitter, along with the more well studied nitric oxide (NO) and carbon monoxide (CO). Intensive studies on its potential as a therapeutic agent for cardiovascular, inflammatory, infectious and neuropathological diseases have been undertaken. Here we review the possible direct targets of H2S in mammals. H2S directly interacts with reactive oxygen/nitrogen species and is involved in redox signaling. H2S also reacts with hemeproteins and modulates metal-containing complexes. Once being oxidized, H2S can persulfidate proteins by adding -SSH to the amino acid cysteine. These direct modifications by H2S have significant impact on cell structure and many cellular functions, such as tight junctions, autophagy, apoptosis, vesicle trafficking, cell signaling, epigenetics and inflammasomes. Therefore, we conclude that H2S is involved in many important cellular and physiological processes. Compounds that donate H2S to biological systems can be developed as therapeutics for different diseases. 

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3. An Examination of Chemical Tools for Hydrogen Selenide Donation and Detection

   https://doi.org/10.3390/molecules29163863  

   Hankins, Rynne; Lukesh, John (August 2024, Molecules)

   Hydrogen selenide (H2Se) is an emerging biomolecule of interest with similar properties to that of other gaseous signaling molecules (i.e., gasotransmitters that include nitric oxide, carbon monoxide, and hydrogen sulfide). H2Se is enzymatically generated in humans where it serves as a key metabolic intermediate in the production of selenoproteins and other selenium-containing biomolecules. However, beyond its participation in biosynthetic pathways, its involvement in cellular signaling or other biological mechanisms remains unclear. To uncover its true biological significance, H2Se-specific chemical tools capable of functioning under physiological conditions are required but lacking in comparison to those that exist for other gasotransmitters. Recently, researchers have begun to fill this unmet need by developing new H2Se-releasing compounds, along with pioneering methods for selenide detection and quantification. In combination, the chemical tools highlighted in this review have the potential to spark groundbreaking explorations into the chemical biology of H2Se, which may lead to its branding as the fourth official gasotransmitter. 

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4. Fluorogenic hydrogen sulfide (H ₂ S) donors based on sulfenyl thiocarbonates enable H ₂ S tracking and quantification

   https://doi.org/10.1039/c8sc05200j  

   Zhao, Yu; Cerda, Matthew M.; Pluth, Michael D. (February 2019, Chemical Science)

   Hydrogen sulfide (H 2 S) is an important cellular signaling molecule that exhibits promising protective effects. Although a number of triggerable H 2 S donors have been developed, spatiotemporal feedback from H 2 S release in biological systems remains a key challenge in H 2 S donor development. Herein we report the synthesis, evaluation, and application of caged sulfenyl thiocarbonates as new fluorescent H 2 S donors. These molecules rely on thiol cleavage of sulfenyl thiocarbonates to release carbonyl sulfide (COS), which is quickly converted to H 2 S by carbonic anhydrase (CA). This approach is a new strategy in H 2 S release and does not release electrophilic byproducts common from COS-based H 2 S releasing motifs. Importantly, the release of COS/H 2 S is accompanied by the release of a fluorescent reporter, which enables the real-time tracking of H 2 S by fluorescence spectroscopy or microscopy. Dependent on the choice of fluorophore, either one or two equivalents of H 2 S can be released, thus allowing for the dynamic range of the fluorescent donors to be tuned. We demonstrate that the fluorescence response correlates directly with quantified H 2 S release and also demonstrate the live-cell compatibility of these donors. Furthermore, these fluorescent donors exhibit anti-inflammatory effects in RAW 264.7 cells, indicating their potential application as new H 2 S-releasing therapeutics. Taken together, sulfenyl thiocarbonates provide a new platform for H 2 S donation and readily enable fluorescent tracking of H 2 S delivery in complex environments. 

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5. The Interplay between Hydrogen Sulfide and Phytohormone Signaling Pathways under Challenging Environments

   https://doi.org/10.3390/ijms23084272  

   Khan, Muhammad Saad; Islam, Faisal; Ye, Yajin; Ashline, Matthew; Wang, Daowen; Zhao, Biying; Fu, Zheng Qing; Chen, Jian (April 2022, International Journal of Molecular Sciences)

   Hydrogen sulfide (H2S) serves as an important gaseous signaling molecule that is involved in intra- and intercellular signal transduction in plant–environment interactions. In plants, H2S is formed in sulfate/cysteine reduction pathways. The activation of endogenous H2S and its exogenous application has been found to be highly effective in ameliorating a wide variety of stress conditions in plants. The H2S interferes with the cellular redox regulatory network and prevents the degradation of proteins from oxidative stress via post-translational modifications (PTMs). H2S-mediated persulfidation allows the rapid response of proteins in signaling networks to environmental stimuli. In addition, regulatory crosstalk of H2S with other gaseous signals and plant growth regulators enable the activation of multiple signaling cascades that drive cellular adaptation. In this review, we summarize and discuss the current understanding of the molecular mechanisms of H2S-induced cellular adjustments and the interactions between H2S and various signaling pathways in plants, emphasizing the recent progress in our understanding of the effects of H2S on the PTMs of proteins. We also discuss future directions that would advance our understanding of H2S interactions to ultimately mitigate the impacts of environmental stresses in the plants. 

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