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.