Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter

Key Points Hydrogen sulfide (H 2 S) is an important signalling molecule; it influences physiological and pathophysiological processes throughout the body. Accurate measurement of hydrogen sulfide remains a challenge, largely because it is highly reactive. H 2 S synthesis from the microbiome contributes substantially to 'tissue levels' of H 2 S. In circumstances of anoxia or hypoxia, H 2 S can 'rescue' mitochondria. H 2 S also exerts important anti-inflammatory and cytoprotective effects while driving the resolution of tissue injury. Animal studies of several H 2 S-releasing drugs show considerable promise for the safe treatment of a wide range of disorders, and several such drugs are now in clinical trials. Coupling of an H 2 S-releasing moiety to other drugs, such as anti-inflammatory drugs, can improve efficacy and/or substantially reduce toxicity. Based on studies in animal models, H 2 S-based drugs may be effective in chemoprevention of cancer, and have also shown promise in the treatment of several neurological disorders, such as Alzheimer disease. Hydrogen sulfide (H 2 S) is a ubiquitous gaseous signalling molecule with a plethora of important roles. In this Review, Wallace and Wang describe the pathways for the synthesis and metabolism of H 2 S and its major mechanisms of action in health and in disease processes, before discussing examples of attempts to exploit the actions of H 2 S in the design of novel drugs. Hydrogen sulfide (H 2 S) has become recognized as an important signalling molecule throughout the body, contributing to many physiological and pathological processes. In recent years, improved methods for measuring H 2 S levels and the availability of a wider range of H 2 S donors and more selective inhibitors of H 2 S synthesis have helped to more accurately identify the many biological effects of this highly reactive gaseous mediator. Animal studies of several H 2 S-releasing drugs have demonstrated considerable promise for the safe treatment of a wide range of disorders. Several such drugs are now in clinical trials.