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ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |Volume XII Issue IX September 2025
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Punica Granatum: A Natural Reservoir of Anti-Inflammatory
Phytoconstituents
T. Malyadri
1
, M. Kishore Babu
2
, D. Bhavana
3
, R. Suvarna Jyothi
3
, K. Reshma
3
, M. Gopi Chandana
3
,
M.Ruchitha
3
1
Associate Professor Qis College of Pharmacy, Ongole, Vengamukkalapalem.
2
Professor & Principal Qis College of Pharmacy, Ongole, Vengamukkalapalem.
3
Research Students Qis College of Pharmacy, Ongole, Vengamukkalapalem.
DOI: https://dx.doi.org/10.51244/IJRSI.2025.120800417
Received: 16 September 2025; Accepted: 24 September 2025; Published: 23 October 2025
ABSTRACT
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.
Keywords: NF-κB, MAPK signaling pathways, COX-2, iNOS, Nrf2
GRAPHICAL ABSTRACT
Graphical abstract summarizing the anti-inflammatory potential of Punica granatum. The fruit provides diverse
phytochemicals (ellagitannins, anthocyanins, flavonoids, punicic acid), which act through multiple
mechanisms (NF-κB, MAPK, COX-2/iNOS, cytokine modulation, Nrf2 activation). Evidence from preclinical
and clinical studies supports its potential role as a natural anti-inflammatory agent.
INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNOVATION (IJRSI)
ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |Volume XII Issue IX September 2025
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INTRODUCTION
Inflammation is a highly conserved biological response designed to protect the body against injury, infection,
and environmental insults. While acute inflammation is protective, chronic and uncontrolled inflammation
contributes to the onset and progression of numerous diseases, including rheumatoid arthritis, atherosclerosis,
diabetes mellitus, neurodegenerative disorders, and certain cancers. Current pharmacological interventions,
such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs), provide symptomatic relief but
are often associated with gastrointestinal toxicity, cardiovascular complications, immunosuppression, and
diminished efficacy over long-term use. This has led to an urgent need for alternative therapeutic strategies
with improved safety and multi-target efficacy. atural products and dietary phytochemicals are increasingly
recognized as potential sources of novel anti-inflammatory agents. Among these, Punica granatum (family:
Lythraceae), commonly known as pomegranate, has been utilized in traditional systems of medicine for
centuries. In Ayurveda and Unani medicine, pomegranate peel, seeds, and juice were prescribed for conditions
such as diarrhea, ulcers, infections, and chronic inflammatory disorders. Modern phytochemical analyses
confirm that the fruit and its parts are abundant in polyphenolic compounds with potent antioxidant and anti-
inflammatory activities.The aim of this review is to systematically analyze the anti-inflammatory potential of
P. granatum by summarizing its phytochemical profile, underlying molecular mechanisms, evidence from
preclinical and clinical studies, applications in nutraceuticals, and prospects for future drug discovery
1,2,3
.
Phytochemical Profile of Punica granatum
The pharmacological potential of P. granatum is largely attributed to its diverse phytoconstituents, distributed
across different parts of the plant such as fruit peel, seeds, juice, leaves, flowers, and bark. Among these, the
peel and juice are particularly enriched with polyphenols, which have been consistently linked to anti-
inflammatory effects
4
.
Table 1. Phytochemical constituents of Punica granatum and their anti-inflammatory actions
Part Used
Major Phytochemicals
Anti-Inflammatory Actions
Peel
Ellagitannins (punicalagin, punicalin), gallic acid, catechins,
flavonols
Strong antioxidant, NF-κB inhibition, cytokine
suppression
Seeds
Fatty acids (punicic acid), sterols, tocopherols, conjugated
linolenic acid
Regulates lipid metabolism, reduces
inflammatory mediators
Juice
Anthocyanins (delphinidin, cyanidin, pelargonidin
glycosides), ellagic acid, vitamin C
Protects endothelial cells, reduces oxidative
stress and cytokines
Flower
Flavonoids, tannins, ursolic acid, gallic acid
Topical anti-inflammatory, wound healing
Bark/Leaves
Alkaloids, tannins, polyphenols, flavonoids
Traditional use in infections, reduces
inflammation in gut and skin
Polyphenols and Ellagitannins
Ellagitannins represent the dominant class of polyphenolic compounds in pomegranate, with punicalagins
being the most abundant and pharmacologically significant constituents. These hydrolyzable tannins are
primarily localized in the peel and juice, contributing significantly to the fruit’s antioxidant capacity. Upon
hydrolysis, punicalagins release ellagic acid, another potent bioactive molecule. Both punicalagins and ellagic
acid have been extensively investigated for their anti-inflammatory and antioxidant properties. Mechanistic
studies demonstrate that they inhibit the activation of the transcription factor nuclear factor kappa B (NF-κB),
leading to downregulation of pro-inflammatory enzymes such as cyclooxygenase-2 (COX-2). Additionally,
these compounds modulate cytokine signaling by suppressing the release of tumor necrosis factor-alpha (TNF-
INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNOVATION (IJRSI)
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α) and interleukin-6 (IL-6), thereby reducing systemic inflammation. Collectively, ellagitannins contribute to
the chemopreventive, cardioprotective, and anti-carcinogenic potential of pomegranate
5
.
Flavonoids
Pomegranate fruit and leaves contain a diverse profile of flavonoids, including quercetin, kaempferol, and
luteolin, which collectively enhance the plant’s therapeutic value. Flavonoids are well-known for their free
radical scavenging activity, effectively neutralizing reactive oxygen species (ROS) and protecting cellular
structures from oxidative injury. Beyond their antioxidant role, flavonoids modulate key intracellular signaling
cascades involved in inflammation, such as mitogen-activated protein kinase (MAPK) and Janus kinase/signal
transducers and activators of transcription (JAK-STAT) pathways. Quercetin, in particular, has been reported
to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophages, thereby attenuating
inflammatory responses. Such activities highlight the role of flavonoids not only as antioxidants but also as
modulators of immune and inflammatory processes, reinforcing their contribution to the health-promoting
effects of pomegranate
6
.
Anthocyanins
The vibrant red coloration of pomegranate juice is attributed to its rich content of anthocyanins, primarily
cyanidin-3-glucoside, delphinidin-3-glucoside, and pelargonidin derivatives. Anthocyanins are water-soluble
pigments with strong antioxidant potential, capable of quenching singlet oxygen and reducing oxidative stress
at the cellular level. Recent studies have expanded their role to include immunomodulatory and anti-
inflammatory effects. In animal models of inflammatory diseases such as colitis and arthritis, anthocyanin
supplementation has been shown to reduce leukocyte infiltration into inflamed tissues and suppress the
expression of pro-inflammatory cytokines. These findings suggest that anthocyanins not only contribute to the
sensory appeal of pomegranate juice but also play a significant role in mediating its therapeutic effects against
chronic inflammatory and autoimmune conditions
7
.
Fatty Acids and Seed Oil Constituents
Pomegranate seed oil is a unique component of the fruit, characterized by its high content of punicic acid, a
conjugated isomer of linolenic acid. In addition to punicic acid, the oil contains bioactive sterols and
tocopherols, which further enhance its nutritional and pharmacological value. Punicic acid has been reported to
exert strong anti-inflammatory activity by suppressing the synthesis of pro-inflammatory eicosanoids, thereby
modulating lipid mediator balance. Furthermore, it improves oxidative stress biomarkers by enhancing
endogenous antioxidant defense systems. The sterols present in seed oil contribute to cholesterol-lowering
effects, while tocopherols act as natural antioxidants, preventing lipid peroxidation. Together, these
constituents make pomegranate seed oil an important dietary and therapeutic agent with potential applications
in managing metabolic, inflammatory, and degenerative disorders
8,9
.
Other Constituents
Additional phytochemicals include tannins, sterols, alkaloids, and triterpenes, many of which may
contribute to the synergistic anti-inflammatory action of whole extracts
10,11,12,13
.
Table 2. Major Phytochemicals of P. granatum with Reported Anti-Inflammatory Activity
Compound/Class
Reported Anti-Inflammatory Activity
Punicalagins
NF-κB inhibition, COX-2 suppression
Ellagic acid
Cytokine modulation, antioxidant
Quercetin
NO inhibition, MAPK regulation
Anthocyanins
Leukocyte infiltration reduction
INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNOVATION (IJRSI)
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Punicic acid
Eicosanoid suppression, antioxidant
Kaempferol
JAK-STAT modulation
Mechanisms of Anti-Inflammatory Activity
The anti-inflammatory activity of P. granatum arises from a multi-targeted approach, involving modulation of
signaling pathways, enzymes, cytokines, and oxidative stress markers
14,15,16,17
.
Figure 1. Anti-inflammatory mechanisms of Punica granatum
Modulation of Pro-Inflammatory Cytokines
Pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-
alpha (TNF-α) play central roles in the initiation and persistence of chronic inflammatory diseases, including
rheumatoid arthritis, inflammatory bowel disease, and metabolic syndrome. Excessive secretion of these
cytokines leads to amplification of the inflammatory cascade, recruitment of immune cells, and tissue damage.
Pomegranate extracts, particularly those enriched in punicalagins, ellagic acid, and anthocyanins, have
demonstrated the ability to significantly reduce the production and secretion of these cytokines in both in vitro
and in vivo studies. This cytokine modulation not only attenuates the local inflammatory response but also
contributes to systemic immune regulation, thereby mitigating disease progression
18
.
NF-κB Pathway Inhibition
The nuclear factor kappa B (NF-κB) signaling pathway is a master regulator of inflammation, orchestrating the
transcription of numerous pro-inflammatory mediators, including cytokines, chemokines, and adhesion
molecules. Aberrant or sustained NF-κB activation is a hallmark of chronic inflammatory and autoimmune
conditions. Bioactive compounds from pomegranate, especially punicalagins and ellagic acid, have been
shown to inhibit the phosphorylation and degradation of IκBα, thereby preventing NF-κB nuclear
translocation. This blockade reduces transcription of downstream inflammatory genes such as cyclooxygenase-
2 (COX-2), inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines. By targeting NF-κB,
pomegranate constituents exert a broad-spectrum anti-inflammatory effect, making this pathway a critical
molecular target for their therapeutic action
19,20
.
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MAPK and JAK-STAT Signaling Regulation
Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun N-
terminal kinase (JNK), and p38 MAPK, are pivotal signaling molecules that transmit extracellular stress and
inflammatory stimuli to the nucleus, thereby regulating cytokine production and inflammatory enzyme
expression. Pomegranate flavonoids and tannins have been reported to attenuate MAPK phosphorylation,
resulting in reduced activation of downstream transcription factors such as AP-1. Additionally, pomegranate
polyphenols influence the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway,
another critical regulator of immune cell activation and cytokine signaling. By interfering with STAT
phosphorylation and nuclear translocation, these compounds suppress aberrant immune responses, thereby
contributing to the attenuation of inflammation. The dual regulation of MAPK and JAK-STAT signaling
highlights the multi-targeted nature of pomegranate bioactives
21
.
Enzyme Inhibition
Inflammatory processes are often perpetuated by overexpression of key enzymes such as cyclooxygenase-2
(COX-2) and inducible nitric oxide synthase (iNOS). COX-2 catalyzes the formation of pro-inflammatory
prostaglandins, while iNOS drives excessive nitric oxide (NO) production, both of which contribute to
vascular dysfunction, oxidative damage, and chronic tissue inflammation. Pomegranate-derived polyphenols,
including ellagic acid and punicalagins, have been shown to suppress the expression and activity of COX-2
and iNOS at both transcriptional and translational levels. This enzymatic inhibition not only reduces the
generation of prostaglandins and NO but also diminishes oxidative stress and inflammatory tissue damage.
Such effects underscore the therapeutic relevance of pomegranate in targeting key inflammatory mediators
22
.
Antioxidant and Nrf2 Pathway Activation
Chronic inflammation is closely linked to oxidative stress, characterized by excessive accumulation of reactive
oxygen species (ROS), which further exacerbate inflammatory signaling. Pomegranate bioactives act as direct
radical scavengers while also activating endogenous antioxidant defense mechanisms. In particular, activation
of the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway has been documented. Upon activation, Nrf2
translocates to the nucleus and binds to antioxidant response elements (ARE), promoting transcription of
antioxidant enzymes such as superoxide dismutase (SOD), catalase, heme oxygenase-1 (HO-1), and
glutathione peroxidase. This upregulation enhances cellular resilience against oxidative stress, indirectly
reducing pro-inflammatory signaling. The combined antioxidant and anti-inflammatory properties of
pomegranate position it as a valuable functional food and nutraceutical candidate for the prevention of
oxidative stress–mediated chronic diseases
23,24
.
Preclinical Evidence
25
In Vitro Studies
Numerous cell-based assays have established the anti-inflammatory potential of P. granatum. Extracts from
peel and juice have been shown to:
Inhibit LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages.
Reduce secretion of TNF-α, IL-1β, and IL-6 in immune cell models.
Suppress COX-2 and iNOS expression in fibroblasts and epithelial cells.
Modulate oxidative stress by scavenging free radicals and enhancing endogenous antioxidant enzymes.
Isolated compounds such as punicalagins and ellagic acid have demonstrated the ability to block NF-κB
activation in stimulated macrophages, while anthocyanins inhibit leukocyte adhesion in endothelial cell assays.
Animal Models
Preclinical studies in rodents provide convincing evidence of pomegranate’s anti-inflammatory efficacy:
INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNOVATION (IJRSI)
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Arthritis models: Pomegranate peel extract reduced paw edema, joint swelling, and cartilage
degradation in collagen-induced arthritis models.
Colitis models: Ellagitannin-rich extracts improved colon histopathology, decreased myeloperoxidase
activity, and lowered cytokine levels in chemically induced colitis.
Dermatitis and skin inflammation: Topical formulations of pomegranate extract reduced erythema,
leukocyte infiltration, and oxidative stress markers.
Metabolic inflammation: In high-fat diet-induced obesity models, pomegranate juice improved insulin
sensitivity and reduced systemic inflammation markers such as CRP and IL-6.
Table 2. Selected Preclinical Studies on Anti-Inflammatory Effects of P. granatum
Model
Extract/Compound
Key Findings
RAW 264.7 macrophages
Punicalagins, ellagic acid
Suppressed NO, TNF-α, IL-6 production
Collagen-induced arthritis (rats)
Peel extract
Reduced joint inflammation and cartilage
erosion
DSS-induced colitis (mice)
Juice extract
Decreased colon inflammation, improved
histology
High-fat diet obesity (rats)
Pomegranate juice
Lowered CRP, improved insulin sensitivity
Clinical Evidence
Although limited compared to preclinical data, human studies provide supportive evidence of pomegranate’s
anti-inflammatory potential.
Rheumatoid and Osteoarthritis
A randomized clinical trial reported that pomegranate juice supplementation significantly reduced disease
activity scores, morning stiffness, and serum inflammatory markers in patients with rheumatoid arthritis. In
osteoarthritis, pomegranate extracts improved joint function and reduced cartilage degradation biomarkers.
Metabolic and Cardiovascular Inflammation
In patients with type 2 diabetes and metabolic syndrome, daily consumption of pomegranate juice or
polyphenol-rich extracts reduced markers of systemic inflammation such as IL-6, CRP, and adhesion
molecules. Improvements in lipid profiles and endothelial function were also noted, suggesting benefits
beyond anti-inflammation.
Gastrointestinal Disorders
Preliminary clinical studies in patients with ulcerative colitis reported symptomatic relief and reduced fecal
calprotectin levels following pomegranate extract supplementation, though larger trials are needed.
Limitations of Clinical Evidence
Most human trials are small-scale, short-duration, and often lack standardized extracts. Variability in
preparation (juice vs. peel extract vs. seed oil) makes it difficult to compare outcomes across studies.
Applications in Herbal Formulations and Nutraceuticals
Pomegranate has been incorporated into a wide range of nutraceuticals and herbal formulations, owing to its
safety and consumer acceptance.
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Dietary supplements: Capsules containing standardized ellagitannin-rich extracts are marketed for joint
health, cardiovascular support, and antioxidant benefits.
Functional foods: Fortified juices, yogurts, and beverages enriched with pomegranate extracts are
widely available.
Topical formulations: Creams and gels containing peel or flower extracts are used for skin
inflammation and wound healing.
Polyherbal combinations: Pomegranate is often combined with curcumin, resveratrol, or green tea
polyphenols for synergistic anti-inflammatory effects.
Challenges include poor bioavailability of punicalagins and ellagic acid, degradation during processing, and
lack of globally accepted quality standards. Novel delivery systems such as nanoparticles, liposomes, and
phytosomes are being investigated to enhance absorption and efficacy.
Research Gaps and Future Perspectives
Despite promising findings, several research gaps remain:
1. Standardization: Extracts vary widely in phytochemical composition depending on cultivar, extraction
method, and plant part used. Establishing standardized formulations is crucial.
2. Pharmacokinetics: The bioavailability of ellagitannins is low; their metabolites (urolithins) may be the
actual bioactive forms. More studies are needed on absorption, metabolism, and tissue distribution.
3. Clinical trials: Most trials are small, short-term, and heterogeneous. Large-scale, multicenter studies are
required to confirm efficacy in chronic inflammatory conditions.
4. Drug development: Isolated compounds such as punicalagins and urolithin A hold promise as lead
molecules for new anti-inflammatory drugs, but require further preclinical and clinical validation.
5. Safety and dosage: While pomegranate is generally safe, optimal therapeutic doses and long-term
safety profiles are not fully established.
Future research should integrate phytochemistry, pharmacology, and clinical sciences to establish P. granatum
as a validated adjunct or alternative to conventional anti-inflammatory therapies.
CONCLUSION
Punica granatum is a phytochemical-rich fruit with significant anti-inflammatory properties, validated through
in vitro, in vivo, and preliminary clinical studies. Its ability to modulate multiple inflammatory pathways,
combined with antioxidant actions, makes it a promising natural therapeutic for chronic inflammatory
disorders. However, issues related to standardization, bioavailability, and clinical validation must be addressed
before it can be widely recommended as a therapeutic agent. With increasing interest in plant-based
interventions and personalized nutrition, pomegranate holds potential not only as a functional food but also as
a source of novel anti-inflammatory drug leads.
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