Mechanisms Underlying the Hydrogen Sulfide Actions: Target Molecules and Downstream Signaling Pathways

As a new important gas signaling molecule like nitric oxide (NO) and carbon dioxide (CO), hydrogen sulfide (H₂S), which can be produced by endogenous H₂S-producing enzymes through l-cysteine metabolism in mammalian cells, has attracted wide attention for long. H₂S has been proved to play an important regulatory role in numerous physiological and pathophysiological processes. However, the deep mechanisms of those different functions of H₂S still remain uncertain. A better understanding of the mechanisms can help us develop novel therapeutic strategies. H₂S can play a regulating role through various mechanisms, such as regulating epigenetic modification, protein expression levels, protein activity, protein localization, redox microenvironment, and interaction with other gas signaling molecules such as NO and CO. In addition to discussing the molecular mechanisms of H₂S from the above perspectives, this article will review the regulation of H₂S on common signaling pathways in the cells, including the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK), Janus kinase (JAK)/signal transducer, and activator of transcription (STAT) signaling pathway. Although there are many studies on the mechanism of H₂S, little is known about its direct target molecules. This article will also review the existing reports about them. Furthermore, the interaction between direct target molecules of H₂S and the downstream signaling pathways involved also needs to be clarified. An in-depth discussion of the mechanism of H₂S and the direct target molecules will help us achieving a deeper understanding of the physiological and pathophysiological processes regulated by H₂S, and lay a foundation for developing new clinical therapeutic drugs in the future. This review focuses on the regulation of H₂S on signaling pathways and the direct target molecules of H₂S. We also provide details on the underlying mechanisms of H₂S functions from the following aspects: epigenetic modification, regulation of protein expression levels, protein activity, protein localization, redox microenvironment, and interaction with other gas signaling molecules such as NO and CO. Further study of the mechanisms underlying H₂S will help us better understand the physiological and pathophysiological processes it regulates, and help develop new clinical therapeutic drugs in the future. Antioxid. Redox Signal. 40, 86-109.