Revista Sextante

An Insight into the Anticancer, Antioxidant, Antidiabetic, Anti-inflammatory, and Mitophagy-Modulating Effects of Urolithin A: A Review

Hafiz Muhammad Usman Abid

School of Pharmaceutical Sciences, Health Services Academy, Islamabad, Pakistan

Muhammad Jawad Ismail

Faculty of Pharmacy, Hamdard University Islamabad, Islamabad, Pakistan

Asma Umer Khayam

Health Services Academy. Islamabad, Pakistan

Farzana khan

Pharmaceutical chemistry, Faculty of Pharmacy Bahauddin Zakariya University Multan, Pakistan; Bakhtawar Amin College of Pharmaceutical Sciences, Multan, Pakistan

Tayyebah Noreen

Bakhtawar Amin College of Pharmaceutical Sciences, Multan, Pakistan; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan

Ahsan Rafiq

Faculty of Pharmacy, Capital University of Science and Technology, Islamabad, Pakistan

Abdul Aziz

University of Poonch Rawalakot, Azad Kashmir, Pakistan

Faisal Rasool

Department of Pathobiology, Faculty of Veterinary and Animal Sciences, University of Poonch Rawalakot, Azad Kashmir, Pakistan

Sajid Ali

Biological Production Division, National Institute of Health, Islamabad, Pakistan

Sobia Abid

Department of Zoology, The Islamia University of Bahawalpur, Rahim Yar Khan Campus, Punjab, Pakistan

Keywords: Urolithin A, anticancer, antioxidant, antidiabetic, anti-inflammatory, mitophagy, gut microbiota, mitochondrial dysfunction, drug delivery

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Abstract

Urolithin A (UA) is a metabolite produced by gut microbes that has garnered attention for its potential to affect cellular signaling in disease and mitochondrial quality control when fed upon dietary ellagitannins and ellagic acid. The present story chronicles critically the evidence on its anticancer, antioxidant, antidiabetic, anti-inflammatory and mitophagic activities, microbial biotransformation, pharmacokinetics, formulation approaches and clinical translation. Preclinical studies suggest that UA could induce changes in the mitochondrial turnover pathway mediated by PINK1/Parkin, and have effects on metabolism pathways mediated by AMPK, on oxidative stress response and on inflammatory pathways mediated by NF-κB and STING-NLRP3. UA decreases proliferation and migration and regulates apoptosis and autophagy in specific models of colorectal cancer, and mitochondrial clearance may contribute to tissue homeostasis or to the adaptation of the cells to the cancer environment. In metabolic and inflammatory animal models, results from studies indicate the potential for enhanced insulin sensitivity and damage to tissues; extrapolation to humans is limited by differences in dose, route and exposures in the animal models. Optimizing drug release or systemic exposure can be achieved via polymeric, liposomal, and emulsion-based delivery systems, but does not necessarily prove clinical superiority. The overall short-term human tolerability and significant alterations in select muscle-performance metrics and mitochondrial biomarkers have been observed, but with no evidence of efficacy in inhibiting cancer, diabetes, or chronic inflammatory disease. Important questions are whether there is inter-individual variation in urolithin formation; whether circulating conjugates are biologically relevant; whether tissues are exposed to unconjugated UA or if there are inter-individual differences in tissue exposures; and whether there are differences between static markers of mitophagy and functional fluxes. Future studies should incorporate validated metabolite quantitation, disease-specific studies with clinically meaningful endpoints, and powered studies for disease-specific formulations with comparable exposure. Nonetheless, before the establishment of the therapeutic value of UA, independent replication, evaluation of the safety in the long-term, and direct determination of mitochondrial function are necessary.