Author(s):
Ferreira, Sofia ; Menezes, Regina ; Trougakos, Ioannis P. ; Gumeni, Sentiljana ; Bolanos-Garcia, Victor M. ; Nunes dos Santos, Claudia ; Ángeles Ávila-Gálvez, María
Date: 2026
Persistent ID: http://hdl.handle.net/10362/191001
Origin: Repositório Institucional da UNL
Subject(s): Cancer; Cardiovascular diseases; Neurodegenerative diseases; Phenolic compounds; Small molecules; UPS; Endocrinology, Diabetes and Metabolism; Biochemistry; Molecular Biology; Nutrition and Dietetics; Clinical Biochemistry; SDG 3 - Good Health and Well-being
Description
Funding Information: This article/publication is based upon work from COST Action ProteoCure, CA20113, supported by COST (European Cooperation in Science and Technology). This research was funded by national funds through FCT\u2014Foundation for Science and Technology, I.P. (Portugal), under the [DOI 10.54499/UIDB/04567/2020] and [DOI 10.54499/UIDP/04567/2020] projects. SF is funded by FCT (UI/BD/151421/2021) and R.M. is funded by the FCT Scientific Employment Stimulus contract [DOI: 10.54499/CEECINST/00002/2021/CP2788/CT0004]. Publisher Copyright: © 2025
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.
