Urolithin A From Gut Metabolite to Therapeutic Agent: Bioavailability, Mechanisms, and Translational Insights

Accumulating evidences have demonstrated that urolithin A (UroA) exerted a wide range of bioactivities, including antioxidant, anti-inflammatory, and mitochondrial function-enhancing effects, thereby highlighting its potential as a therapeutic agent for various diseases. Preclinical studies have shown that UroA induced mitophagy both in vitro and in vivo, preventing age-associated mitochondrial dysfunction and improving lifespan and muscle function as well as enhancing exercise capacity. However, its clinical application is limited by poor oral bioavailability and considerable interindividual variability in microbial conversion, as pharmacokinetic studies indicated low plasma exposure under standard administration. Moreover, approximately 10% of individuals are classified as urolithin nonproducers, independent of age, posing an additional challenge for clinical translation. To overcome those limitations, formulation strategies such as nanoparticles and liposomes have been developed, resulting in several-fold increases in systemic bioavailability compared with unformulated UroA. This review would provide a comprehensive overview of recent advances in the metabolism of UroA, current approaches to improve its bioavailability, safety evaluations, and elucidated the underlying mechanisms of its bioactivities. Furthermore, recent progresses in chemical and biotechnological synthesis strategies of UroA are also summarized. These insights will provide a scientific foundation for further utilization of UroA for human health.