Modulation of the Ubiquitin-Proteasome System by Circulating (Poly)phenol-Derived Metabolites: Implications for Chronic Diseases.

The ubiquitin-proteasome system (UPS) is a key cellular mechanism responsible for protein turnover, with essential roles in cell cycle regulation, gene expression, and responses to oxidative and inflammatory stress. UPS dysregulation is implicated in the pathogenesis of multiple chronic diseases, including neurodegenerative, cardiovascular, and oncological disorders. This review examines the emerging role of circulating polyphenol-derived metabolites, such as valerolactones (from flavan-3-ols), benzoic acid derivatives, urolithins (from ellagitannins), and hydroxycinnamic acids (e.g., ferulic and caffeic acids), as modulators of UPS activity. We summarize experimental evidence demonstrating their ability to affect proteasome function through diverse mechanisms, including autophagy induction, modulation of ubiquitination-related enzymes, and attenuation of oxidative or inflammatory signals. While bioavailability studies have described the absorption and metabolism of dietary polyphenols, less is known about which specific metabolites reach target tissues at biologically active concentrations capable of modulating the UPS. In addition, current knowledge is primarily based on cellular models (e.g., endothelial cells, myotubes, macrophages, cancer cell lines) and in vivo studies in rodents, often using supraphysiological doses or isolated compounds. To translate these findings into therapeutic applications, further research is needed to integrate mechanistic insights from preclinical models with data from human clinical studies, taking into account physiologically relevant concentrations, chronic exposure patterns, and tissue-specific distribution. Such approaches could help unlock the potential of (poly)phenol-derived metabolites as regulators of proteostasis in chronic disease.