Human Serum Albumin: The Role of Cys34 and Nucleophilic Sites in Oxidative Stress and in the Detoxification of Endogenous and Xenobiotic Electrophilic Compounds

Dear Colleagues,

Human serum albumin (HSA) contains reactive nucleophilic sites including a single unbound cysteine residue—Cys34—and several accessible and reactive Lys, His, and Arg residues. Cys34 serves as the primary source of thiols in the bloodstream, accounting for approximately 80% of the total thiol pool. This residue is highly reactive and is capable of interacting with both radical and non-radical oxidants, as well as electrophilic compounds. The reduced form of albumin, known as mercaptoalbumin (HSA-SH), is a key regulator of the redox state in extracellular compartments, including plasma and interstitial fluids. Even under physiological conditions, HSA-SH undergoes significant oxidation, forming both reversible (mainly cysteinylated—HSA-S-S-Cys) and irreversible derivatives (such as sulfinic and sulfonic forms). These oxidative modifications increase notably with age and in conditions characterized by oxidative stress. Alterations in the levels of Cys34 and its oxidative forms have been observed in various oxidative stress-related diseases, including cardiovascular disease and chronic kidney disease. 

In addition to Cys34, albumin contains several other accessible and reactive nucleophilic sites (Lys, His, and Arg residues), which, together with Cys34, form a pool of residues that is capable of interacting with endogenous and xenobiotic electrophilic compounds, thereby serving as a first line of metabolic defense against potentially damaging molecules. 

Despite these advances, several key aspects require further investigation, i.e., the precise role of Cys34 and its nucleophilic sites acting as regulators of the extracellular redox state and acting as acceptors of reactive endogenous or xenobiotic electrophilic compounds; the biological activity of albumin–electrophilic adducts; the endogenous mechanisms that maintain the balance between the reduced and oxidized forms, as well as between free and conjugated forms; the contribution of albumin nucleophilic sites to the development and progression of oxidative stress-based diseases; and the pharmacological potential of treatments that restore mercaptoalbumin and the nucleophilic sites. 

We invite researchers to contribute critical reviews and original research articles on recent advances in the study of Cys34 oxidative modifications.

Potential topics include, but are not limited to, the following:

• Analytical methods for measuring modifications of albumin nucleophilic sites.
• Cys34 and its modifications as biomarkers of systemic oxidative stress.
• Pharmacological strategies to regenerate mercaptoalbumin from its oxidized states.
• The impact of environmental stressors on the modifications of albumin nucleophilic sites.
• The role of modifications to albumin nucleophilic sites in disease pathophysiology.
• Endogenous mechanisms for maintaining mercaptoalbumin levels.
• Albumin nucleophilic sites as detoxifying agents of endogenous and exogenous electrophilic compounds.
• Biological effect of albumin–electrophilic adducts.

Prof. Dr. Giancarlo Aldini
Dr. Alessandra Altomare
Dr. Giovanna Baron
Guest Editors

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• Cys34
• cysteine residue
• mercaptoalbumin
• oxidative stress
• oxidative stress-based diseases