Sulfhydrated albumin transmits H(2)S signaling and ameliorates DOX-induced multiorgan injuries.

Hydrogen sulfide (H(2)S) is a vital signaling molecule involved in various physiological processes; however, the mechanisms underlying its systemic signaling remain poorly understood. We hypothesized that albumin, the predominant plasma protein and a vital sulfhydryl carrier, mediated systemic H(2)S signaling, which could potentially treat H(2)S-deficient diseases. This study aimed to investigate this hypothesis. Our results showed the presence of sulfhydrated proteins in normal mouse serum, with albumin being particularly enriched. The level of sulfhydration was influenced by H(2)S availability and the redox environment. In vitro incubation of albumin with NaHS resulted in an increased number of sulfhydrated groups. Under reductive conditions, this sulfhydrated albumin (-SSH-Alb) released substantial amounts of H(2)S. When -SSH-Alb was added to cultured endothelial cells, it activated the cAMP signaling pathway, upregulated cystathionine γ-lyase (CSE) expression, and enhanced intracellular H(2)S levels. In an in vitro inflammatory model involving macrophages and endothelial cells, -SSH-Alb inhibited macrophage adhesion, reduced LPS-induced expression of adhesion molecules, and suppressed cytokine production and inflammasome activation. These effects correlated with improved cellular redox status. Furthermore, in vivo administration of -SSH-Alb protected mice from doxorubicin (DOX)-induced cardiotoxicity and intestinal damage. It improved mouse mortality, and alleviated ferroptotic cardiac injury and gut barrier dysfunction. These therapeutic benefits were associated with rebalanced local and systemic redox status. In summary, our study reveals that -SSH-Alb reserves, transmits, and amplifies H(2)S signals and exhibits significant anti-inflammatory and antioxidant properties. This characteristic of -SSH-Alb holds promise for preventing and treating a wide range of diseases.