Protein persulfidation: Rewiring the hydrogen sulfide signaling in cell stress response

The past few decades have witnessed significant progress in the discovery of hydrogen sulfide (H₂S) as a ubiquitous gaseous signaling molecule in mammalian physiology, akin to nitric oxide and carbon monoxide. As the third gasotransmitter, H₂S is now known to exert a wide range of physiological and cytoprotective functions in the biological systems. However, endogenous H₂S concentrations are usually low, and its potential biologic mechanisms responsible have not yet been fully clarified. Recently, a growing body of evidence has demonstrated that protein persulfidation, a posttranslational modification of cysteine residues (RSH) to persulfides (RSSH) elicited by H₂S, is a fundamental mechanism of H₂S-mediated signaling pathways. Persulfidation, as a biological switch for protein function, plays an important role in the maintenance of cell homeostasis in response to various internal and external stress stimuli and is also implicated in numerous diseases, such as cardiovascular and neurodegenerative diseases and cancer. In this review, the biological significance of protein persulfidation by H₂S in cell stress response is reviewed providing a framework for understanding the multifaceted roles of H₂S. A mechanism-guided perspective can help open novel avenues for the exploitation of therapeutics based on H₂S-induced persulfidation in the context of diseases.