Shedding Light Towards the Power of Phenolic Metabolites as Dynamic Modulators of the Ubiquitin-Proteasome System in Chronic Diseases

The ubiquitin-proteasome system (UPS) is a critical cellular mechanism involved in protein turnover, influencing processes such as cell cycle regulation, gene expression, and stress responses. Dysregulation of the UPS contributes to the pathogenesis of chronic diseases, including neurodegeneration, cardiovascular disorders, and cancer. This review explores the potential of circulating phenolic metabolites — bioactive metabolites derived from dietary (poly)phenols — as modulators of UPS activity. Using comprehensive analysis, we summarize evidence linking phenolic metabolites, such as valerolactones, benzoic acids, urolithins, and hydroxycinnamic acids, to proteasome modulation through mechanisms like autophagy activation, inflammatory mediator reduction, and oxidative stress prevention. Despite the growing interest, significant gaps remain, including limited data on physiological concentrations, metabolite availability, and exposure conditions in cellular and in vivo models. Advancing the understanding of phenolic metabolites in UPS regulation could unlock new therapeutic strategies for managing chronic diseases, highlighting the need for further research integrating clinical and mechanistic insights.