Punica Granatum: A Natural Reservoir of Anti-Inflammatory Phytoconstituents

Inflammation is a central pathological process underlying several acute and chronic diseases, ranging from arthritis and inflammatory bowel disease to cardiovascular and metabolic disorders. Conventional anti-inflammatory therapies, though effective, are often limited by adverse effects and incomplete disease resolution, prompting the search for safer and multi-targeted alternatives. Punica granatum (pomegranate), a fruit-bearing shrub widely cultivated across Asia and the Mediterranean, has attracted substantial attention as a functional food and phytopharmaceutical resource. Rich in ellagitannins, flavonoids, anthocyanins, and other phenolic constituents, pomegranate exhibits broad-spectrum anti-inflammatory effects demonstrated in cell-based assays, animal models, and human clinical studies. The mechanisms of action are diverse and include suppression of pro-inflammatory cytokines, inhibition of NF-κB and MAPK signaling pathways, downregulation of COX-2 and iNOS, and enhancement of antioxidant defense via the Nrf2 pathway. This review provides a comprehensive evaluation of the phytochemistry, mechanistic pathways, preclinical studies, and clinical trials investigating the anti-inflammatory potential of P. granatum. Applications in nutraceuticals, formulation challenges, and prospects for drug discovery are also highlighted.

NF-κB, MAPK signaling pathways, COX-2, iNOS, Nrf2

1. Ansky EP, Newman RA. Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer. J Ethnopharmacol. 2007;109(2):177-206. doi:10.1016/j.jep.2006.09.006 [Google Scholar] [Crossref]

2. Aviram M, Dornfeld L, Kaplan M, Coleman R, Gaitini D, Nitecki S, et al. Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and in atherosclerotic mice. Am J Clin Nutr. 2000;71(5):1062-76. doi:10.1093/ajcn/71.5.1062 [Google Scholar] [Crossref]

3. Aviram M, Rosenblat M, Gaitini D, Nitecki S, Hoffman A, Dornfeld L, et al. Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr. 2004;23(3):423-433. doi:10.1016/j.clnu.2003.10.002. [Google Scholar] [Crossref]

4. Aviram M, Rosenblat M. Pomegranate for cardiovascular protection: antioxidant and antiatherogenic activities. Oxid Med Cell Longev. 2012;2012:382763. doi:10.1155/2012/382763 [Google Scholar] [Crossref]

5. BenSaad LA, Kim KH, Quah CC, Kim WR, Shahimi M. Anti-inflammatory potential of ellagic acid, gallic acid and punicalagin in LPS-stimulated RAW 264.7 macrophages. BMC Complement Altern Med. 2017;17:199. doi:10.1186/s12906-017-1706-7 [Google Scholar] [Crossref]

6. Čolić M, Stojanović S, Petrović D, et al. Immunomodulatory activity of punicalagin, punicalin and other ellagitannins from pomegranate peel. Int J Mol Sci. 2022;23(22):14113. doi:10.3390/ijms232214113 [Google Scholar] [Crossref]

7. Cordiano R, Carullo G, Sciortino MT, et al. Pomegranate (Punica granatum L.) extract exerts neuroprotective and anti-inflammatory effects in vitro. Molecules. 2024;29(17):4174. doi:10.3390/molecules29174174 [Google Scholar] [Crossref]

8. D’Angelo G, Morana O, Crupi R, et al. Pomegranate extract and its combination with other nutraceuticals: impact on inflammatory biomarkers. Nutrients. 2023;15(4):1092. doi:10.3390/nu15041092 [Google Scholar] [Crossref]

9. Gardeli C, Papageorgiou V, Giannoulis K, et al. Anthocyanin stability and profiles in pomegranate juices from different cultivars. Food Chem. 2019;277:886-893. doi:10.1016/j.foodchem.2018.11.047 [Google Scholar] [Crossref]

10. Huang M, Xie S, Zhang Z, Yang Y, Liu Y, Sun S. Punicalagin inhibits inflammation and migration of fibroblast-like synoviocytes by suppressing NF-κB signaling: potential therapeutic effects for rheumatoid arthritis. Int Immunopharmacol. 2021;99:107977. doi:10.1016/j.intimp.2021.107977 [Google Scholar] [Crossref]

11. Kang B, Seo J, Lee J, et al. Punicalagin regulates pro- and anti-inflammatory cytokines and activates Nrf2/Keap1 signaling in mice. Int J Mol Sci. 2019;20(17):4281. doi:10.3390/ijms20174281 [Google Scholar] [Crossref]

12. Liu W, Zhang H, Zhang W, Yang M, Ma H, Wang S. Punicalagin attenuates oxidative stress and inflammation via NF-κB and Nrf2 signaling. Front Pharmacol. 2021;12:697307. doi:10.3389/fphar.2021.697307 [Google Scholar] [Crossref]

13. Mahdavi A, Dolatkhah S, Vafa M, Nadjarzadeh A, Nasir Y, Foroumandi E, et al. Effects of pomegranate (Punica granatum) on clinical and biochemical outcomes in human and animal studies: a systematic review. Front Nutr. 2021;8:669448. doi:10.3389/fnut.2021.669448 [Google Scholar] [Crossref]

14. Medarametla RT, Venkata Gopaiah K, Harshad S, Lakshmi R. Development of ondansetron tablets with advanced disintegrant technology for rapid release and improved pharmacokinetics. South Eastern Eur J Public Health. 2025;1(1):1-12. [Google Scholar] [Crossref]

15. Minutolo A, Ciarcia R, Squillaci G, et al. Phytocomplexes from pomegranate: characterization and antioxidant activity. Antioxidants (Basel). 2023;12(7):1560. doi:10.3390/antiox12071560 [Google Scholar] [Crossref]

16. Moradnia M, Ghadami MR, Rezaei A, et al. The power of Punica granatum: updated review on phytochemistry and therapeutic potential. Comp Biochem Physiol C Toxicol Pharmacol. 2024;274:109586. doi:10.1016/j.cbpc.2024.109586 [Google Scholar] [Crossref]

17. Rahimi HR, Arastoo M, Saeidnia S. A comprehensive review of Punica granatum (pomegranate) properties in toxicological, pharmacological, cellular and molecular biology researches. Evid Based Complement Alternat Med. 2012;2012:1-16. doi:10.1155/2012/682858 [Google Scholar] [Crossref]

18. Sahebkar A, Ferri C, Giorgini P, Bo S, Nachtigal P, Grassi D. Effects of pomegranate supplementation on inflammatory biomarkers: a systematic review and meta-analysis of randomized controlled trials. Phytother Res. 2020;34(9):2176-2188. doi:10.1002/ptr.6663 [Google Scholar] [Crossref]

19. Shabir I, Lone SH, Khuroo MA, et al. Bioactive potential of punicalagin: a comprehensive review on pharmacological activities and mechanisms. Food Sci Nutr. 2024;12(3):1185-1204. doi:10.1002/fsn3.3678 [Google Scholar] [Crossref]

20. Shukla M, Gupta K, Rasheed Z, Khan KA, Haqqi TM. Consumption of pomegranate extract suppresses NF-κB and IL-6 in experimental models of lung inflammation. Front Nutr. 2022;9:829275. doi:10.3389/fnut.2022.829275 [Google Scholar] [Crossref]

21. Sun DP, Zhao J, Wang Y, et al. Punicalagin suppresses NF-κB signaling to inhibit osteosarcoma cell proliferation and induce apoptosis. Sci Rep. 2024;14:5152. doi:10.1038/s41598-024-61834-7 [Google Scholar] [Crossref]

22. Tang L, Li X, Li L, Peng W, Peng Y, Chen J. Punicalagin alleviates psoriasis by inhibiting NF-κB-mediated IL-1β transcription and caspase-1-regulated IL-1β secretion. Front Pharmacol. 2022;13:817526. doi:10.3389/fphar.2022.817526 [Google Scholar] [Crossref]

23. Valero-Mendoza AG, Ramírez-Flores LM, Salinas-Salinas J, et al. The whole pomegranate (Punica granatum L.): phytochemistry, analytical methods and biological properties. Food Chem. 2023;409:135252. doi:10.1016/j.foodchem.2022.135252 [Google Scholar] [Crossref]

24. Venkata Gopaiah K, Mandadapu G, Kolli P. Development, evaluation and characterization of buccal patches containing nebivolol using hydrophilic polymers. Int J Appl Res. 2025;11(2):129-36. [Google Scholar] [Crossref]

25. Venkata Gopaiah K, Medarametla RT, Suresh Kumar JN. Advanced granulation and formulation strategies for histamine H2 receptor antagonists in peptic ulcer disease management. J Neonatal Surg. 2025;14(10S):1000-13. [Google Scholar] [Crossref]

26. Venkata Gopaiah K, Medarametla RT, Suresh Kumar JN. Formulation and evaluation of controlled release matrix tablets of fosinopril by using hydrophilic polymer. J Neonatal Surg. 2025;14(10S):978-92. [Google Scholar] [Crossref]

27. Venkata Gopaiah K. Review on a novel approach in pharmaceutics: nanofibers—advances, applications, and future prospects. Preprint. 2025;1(1):21-7. [Google Scholar] [Crossref]

28. Venusova E, Asher R, Zelenkova N, Liskova A, Kubatka P, Büsselberg D. Punicalagin and its anti-inflammatory effects: molecular evidence for NF-κB and MAPK inhibition. Nutrients. 2021;13(7):2150. doi:10.3390/nu13072150 [Google Scholar] [Crossref]

29. Xu J, Zeng L, Xiao K, Gao Y, He D, Li Y. Punicalagin regulates signaling pathways in inflammation and shows promise for treating inflammation-associated chronic diseases: a review. Front Pharmacol. 2021;12:697622. doi:10.3389/fphar.2021.697622 [Google Scholar] [Crossref]

30. Yousefi M, Sadriirani M, PourMahmoudi A, et al. Effects of pomegranate juice on inflammatory biomarkers and complete blood count in patients with COVID-19: study protocol for a randomized controlled trial. Trials. 2021;22:586. doi:10.1186/s13063-021-05560-8 [Google Scholar] [Crossref]

• Development and Evaluation of Floating Alginate Beads of Esomeprazole
• Determination of pKa Value for Ranolazine and Atenolol Using UV Spectroscopy
• The Science of Sustained-Release Medications
• Development of Proteomics in Clinical Medicine
• Advances on Quinoline Derivatives: A Review of Synthesis and Biological Activities