Pharmacology of Hydrogen Sulfide and Its Donors in Cardiometabolic Diseases

Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H₂S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H₂S in regulating proteins via persulfidation, a well-known modification intricately associated with the pathogenesis of CMDs. This review seeks to investigate recent updates on the physiological actions of endogenous H₂S and the pharmacological roles of various H₂S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies including multi-omics, intestinal microflora analysis, organoid and single-cell sequencing techniques are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H₂S in health and diseases. We will critically assesse the current literatures to clarify the roles of H₂S in diseases while also delineating the opportunities and challenges they present in H₂S-based pharmacotherapy for CMDs. Significance Statement The comprehensive review covers recent developments in H₂S biology and pharmacology in CMDs. Endogenous H₂S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H₂S.