Hydrogen sulfide-mediated protein s-persulfidation: a regulatory mechanism in cardiovascular homeostasis

Cardiovascular diseases represent a primary cause of global mortality. Hydrogen sulfide operates as a major endogenous gasotransmitter that contributes to cardiovascular homeostasis through multiple biochemical mechanisms, among which protein S-persulfidation, represents a major redox-sensitive post-translational mechanism. This dynamically reversible modification converts cysteine sulfhydryl groups into highly nucleophilic persulfide groups to prevent irreversible oxidative damage.

This review aims to systematically synthesize the current molecular understanding of S-persulfidation in cardiovascular biology. We evaluate the methodological evolution of site-specific detection technologies, delineate the regulatory mechanisms of sulfur signaling across distinct physiological axes, and assess the clinical translational potential of reactive sulfur species delivery systems.

The manuscript outlines the evolution of detection methodologies from early biotin-switch assays to Quantitative Thiol Reactivity Profiling. Mechanistically, S-persulfidation modulates membrane potential and vascular tone by altering the open probability of ion channels including K_ATP and Ca_v1.2. At the intracellular level, this modification regulates kinase cascades, redox sensors such as the Keap1/Nrf2 pathway, and metabolic enzymes to preserve mitochondrial bioenergetics. S-persulfidation also orchestrates genomic and post-transcriptional programs by directly modifying transcription factors and RNA-binding proteins. Furthermore, it reinforces the cellular protein quality control system to alleviate endoplasmic reticulum stress, optimize autophagy, and establish inhibitory checkpoints against apoptosis and pyroptosis. The review also evaluates systemic delivery vectors, including S-persulfidated albumin and engineered biomaterial scaffolds. Overcoming current translational barriers requires integrating spatial multi-omics with site-specific genetic validation to advance S-persulfidation biology toward precise cardiovascular therapeutics.