H₂S-mediated protein S-sulfhydration: a novel regulatory module in lipid metabolism

H₂S-mediated protein S-sulfhydration is an emerging post-translational modification that regulates key biological processes via regulating enzyme activities, controlling protein-protein interactions, and modulating signal transduction. Lipid metabolism represents an important target of S-sulfhydration-mediated regulation, which fine-tunes lipid metabolic networks including fatty acid turnover, triglyceride metabolism, and cholesterol homeostasis. This review aims to systematically summarize current knowledge on the regulation of lipid metabolism with a focus on S-sulfhydration, and highlight novel molecular targets identified in recent research. By integrating emerging evidence, we demonstrate how S-sulfhydration acts as a regulatory module linking redox signaling and lipid homeostasis, which may be leveraged therapeutically to treat lipid-associated disorders, either using H₂S donors or sulfhydrated protein-targeted medications.