Punicalagin: Structure, Metabolism, and Therapeutic Potential of a Major Pomegranate Ellagitannin

Punicalagin, the predominant ellagitannin of pomegranate ( Punica granatum L .), shows strong therapeutic potential in chronic diseases, yet medical implementation and therapeutic development remain limited due to poor bioavailability and inconsistent responses in gut-derived metabolites. This review consolidates recent findings (2000–2025) on punicalagin’s biochemical structure, metabolism, therapeutic mechanisms, and delivery strategies. Distinct α / β anomeric forms, together with redox-active hexahydroxydiphenoyl (HHDP) groups linked to a glucose core, underpin punicalagin’s antioxidant and anti-inflammatory activities, with the isomers differing in stability and receptor interactions. Preclinical studies on anticancer demonstrate their effects through NF-κB and STAT3 inhibition, apoptosis induction, and synergy with conventional therapies. Clinical responses vary according to urolithin metabotype, with urolithin A most validated, while urolithin B, C, and D show more limited evidence, highlighting the need for personalized nutrition approaches. Bioavailability has been improved using chitosan nanoparticles and lipid-based self-microemulsifying drug delivery systems (SMEDD), a lipid-based nanoemulsion that enhances lymphatic transport and bypasses first-pass metabolism. Key research areas requiring further study, including standardized preparations, large-scale human trials, clarifying microbiome-dependent variability in urolithin production and sustainable production from pomegranate waste. Punicalagin thus represents a promising nutraceutical candidate, requiring optimized delivery and precision nutrition strategies to achieve clinical adoption.