Unveiling the Anticancer Potential of Urolithin A in Colorectal Cancer: A Systematic Review

Colorectal cancer (CRC) is a major global health burden, and Urolithin A (Uro-A) has emerged as a promising anticancer agent. This systematic review aims to synthesize current in vitro evidence on the anticancer effects of Uro-A in CRC, highlighting effective concentration ranges, exposure times, relevant outcomes, and underlying molecular mechanisms.

Following PRISMA 2020 guidelines, a systematic search was conducted in PubMed, Scopus, and Web of Science using the following strategy: (colorectal cancer) AND (urolithin a) OR (3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one). Eligibility criteria were defined by the PICO framework: (P) in vitro CRC cell models; (I) Uro-A alone or combined treatments; (C) No intervention, vehicle or other treatments; (O) Relevant anticancer outcomes of Uro-A in CRC. Only original, full-text, in vitro studies in English were included. Risk of bias was assessed using ToxRTool. A qualitative synthesis was performed due to the heterogeneity of the included studies.

Fifteen studies met inclusion criteria, involving CRC cell lines (Caco-2, HCT-116, HT-29, SW480, SW620) and normal colon fibroblasts (CCD18-Co). Uro-A inhibited CRC cell proliferation, clonogenic growth, cancer stem cells properties, migration, and invasion, and induced cell cycle arrest, apoptosis, autophagy, and senescence, through modulation of key signaling pathways and proteins. Co-treatments with conventional chemotherapeutics and microbiota-derived metabolites showed additive or synergistic effects.

The findings support Uro-A’s potential as a preventive or adjuvant agent in CRC treatment. However, preclinical nature of the evidence and methodological heterogeneity hinder clinical extrapolation to in vivo contexts. Human clinical trials are necessary to overcome these limitations.

This review was registered in PROSPERO (CRD420251070874) and supported by FCT/MCTES UIDP/05608/2020 and UIDB/05608/2020. Institutional.