S-sulfhydration: Novel insights into the antioxidant and antiinflammation in age-related diseases

Hydrogen sulfide (H₂S) and hydrogen polysulfide-induced S-sulfhydration are critical posttranslational modifications that specifically target cysteine residues within proteins. Degenerative diseases are often characterized by oxidative stress and inflammaging, ultimately leading to progressive organ dysfunction. Emerging evidence underscores the essential role of S-sulfhydration in modulating mitochondrial synthesis, energy metabolism, and cellular homeostasis during aging. However, the intricate pathways and molecular regulators that connect S-sulfhydration to degenerative pathologies remain insufficiently elucidated.

This review aims to delineate the biological significance of S-sulfhydration in the context of age-associated degenerative disorders especially in redox balance and inflammatory response, including neurodegenerative diseases, osteoarthrosis, osteoporosis, and age-related renal pathologies. In addition, the redox-adaptive S-sulfhydration and clinical applications based on S-sulfhydration-related delivery strategies are proposed, which may reveal novel therapeutic interventions in combating aging.

This review provides a detailed synthesis of the cellular and molecular mechanisms by which S-sulfhydrated target proteins mitigate senescence phenotypes through antioxidative and anti-inflammatory pathways. Nonetheless, the dual role of S-sulfhydration highly depends on threshold-dependent signaling correlated with H₂S synthetase. Moreover, the dynamic compensatory mechanism of S-sulfhydration plays a critical role in the interaction between oxidative stress and inflammatory stress during the aging process, which identifies S-sulfhydration-mediated redox homeostasis as a promising avenue for therapeutic interventions aimed at mitigating the progression of degenerative diseases.