Review Article
Targeting the NF-κB–Epigenetic axis using nutraceutical in chronic
inflammatory disease management
Maya G. Pillai1, S. Abhirami1, D.S. Amrutha1, Mani Sebastian1, R. Haritha1, D. Aashish2,
V.S. Salu1, Yara Nader1, Akhlaq A. Mehras1, Helen Antony1
1Department of Biochemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram,
2Department of Zoology, Mahatma Gandhi College, Thiruvananthapuram, Kerala, India
Corresponding author: Helen Antony, Email: helenabios@keralauniversity.ac.in
Journal of Experimental Biology and Zoological Studies. 2(2): p 128-41, Jul-Dec 2026.
Received: 01/05/2026; Revised: 17/06/2026; Accepted: 19/06/2026; Published: 05/07/2026
______________________________________________________________________________
Abstract
Chronic inflammatory diseases, including cardiovascular disorders, metabolic syndrome,
autoimmune diseases, cancer, and neurodegenerative conditions, are driven largely by continuous
activation of nuclear factor kappa-B (NF-κB) signalling. While NF-κB is recognized as a
transcription factor regulating immune and inflammatory gene expression, emerging evidence
demonstrates that NF-κB activity is tightly controlled through epigenetic mechanisms such as
DNA methylation, histone modifications, chromatin remodelling, and non-coding RNA
regulation. Dietary polyphenols have gained increasing attention as epigenetic modulators of this
NF-κB signalling pathway. This review focuses on current advances in understanding how dietary
polyphenols including resveratrol, curcumin, epigallocatechin gallate (EGCG), quercetin,
genistein, fisetin, luteolin, and epicatechin regulate inflammatory signalling through epigenetic
reprogramming. These compounds influence DNA methyltransferases, histone acetyltransferases,
histone deacetylases, Silent Information Regulator T1(SIRT1) activation, and microRNA
networks, ultimately reducing NF-κB p65 acetylation, suppressing transcriptional activation of
pro-inflammatory genes, and restoring immune homeostasis. Evidence from experimental studies
reveal the potential of these polyphenols in managing chronic inflammatory disorders like
atherosclerosis, type 2 diabetes, rheumatoid arthritis, cancer, and neuroinflammatory disorders.
Despite promising insights, translational challenges remain, including limited bioavailability,
variability in metabolism, optimal dosing strategies, and potential epigenome-wide effects. Future
studies integrating nutrigenomics, epigenomics, systems biology, and clinical trials are required to
validate polyphenol-based interventions. Targeting the NF-κB–epigenetic axis is an innovative
strategy for precision therapeutics and management of chronic inflammatory diseases through
dietary and nutraceutical approaches.
Keywords: NF-κB; Epigenetic regulation; Nutraceutical polyphenols; Chronic inflammation;
DNA methylation; Histone modification.
______________________________________________________________________________
Introduction
Inflammation is the immune system's response to harmful stimuli, such as pathogens, damaged
cells, toxic compounds, or irradiation,[1] and acts by removing injurious stimuli and initiating the
healing process.[2] Inflammation is therefore a vital defence mechanism for health. Acute
inflammation has a rapid onset, typically resolves within a few days, exhibits typical signs and
symptoms, and is characterised by a cellular infiltrate primarily consisting of neutrophils.[3] The
erythema observed in acute inflammation results from increased blood flow triggered by various
mediators, like histamine acting on vascular smooth muscle cells. This process initially affects the
arterioles and opens new capillary beds in the affected area.[4] Lymphatic vessels are active in
acute inflammation. During inflammation, lymph flow increases, facilitating the drainage of
oedema fluid that accumulates as a result of increased vascular permeability.
Along with fluid, leukocytes, cell debris, and microbes may also enter the lymph.[5] Similar to
blood vessels, lymphatic vessels proliferate during inflammatory reactions to handle the increased
load[6]. Thus, the acute inflammation is a protective mechanism that removes the injurious stimuli
and initiates a healing process, restoring the homeostasis of the organism.[2. Uncontrolled acute
inflammation, however, can become chronic, and may provide the basis of a variety of serious,
chronic diseases.[4–6]
Chronic inflammatory diseases constitute a major global health challenge, contributing
significantly to morbidity and mortality worldwide. It is estimated that approximately 43 million
individuals were affected by these diseases in 2021, accounting for more than 75% of non-
pandemic deaths globally. In the same year, 18 million deaths occurred before the age of 70, of
which 82% were reported in low- and middle-income countries. Cardiovascular diseases were the
leading cause of mortality among non-communicable diseases (NCDs) causing 19 million deaths,
followed by cancers (10 million), chronic respiratory diseases (4 million), and diabetes (over 2
million including kidney disease deaths caused by diabetes). Together, these four groups of
diseases accounted for 80% of all premature NCD deaths.[7]
Despite advances in pharmacological therapy, existing treatments mainly focus on slowing disease
progression, managing complications, and controlling risk factors rather than reversing by
addressing upstream molecular regulators of inflammation.[8] Persistent activation of inflammatory
signalling pathways results in cytokine imbalance, oxidative stress, endothelial dysfunction, and
progressive organ damage.[9]
The transcription factor nuclear factor-κB (NF-κB) functions as a master regulator of inflammation
by controlling genes involved in immune activation, cell survival, and stress responses.[10]
Dysregulated NF-κB signalling has been implicated in chronic inflammatory disorders like
atherosclerosis, chronic obstructive pulmonary disease, chronic kidney disease, metabolic
disorders, and neurodegenerative conditions.[11]
Recent discoveries highlight that inflammatory signalling is not governed solely by genetic
mechanisms but is profoundly influenced by epigenetic regulation. DNA methylation patterns,
histone modifications, and microRNA networks determine chromatin accessibility and
transcriptional activation of inflammatory genes. Importantly, epigenetic modifications are
dynamic and responsive to environmental and dietary factors.[12,13]
Nutraceutical polyphenols—bioactive compounds abundant in fruits, vegetables, tea, spices, and
medicinal plants—have attracted considerable interest for their ability to modulate epigenetic
enzymes and signalling pathways. Rather than acting merely as antioxidants, these compounds
influence transcriptional programming of inflammatory pathways, particularly the NF-κB
axis.[14,15]
Chronic inflammatory diseases are increasingly understood not merely as conditions of persistent
immune activation but as disorders of maladaptive inflammatory memory. Repeated
environmental, metabolic, and lifestyle stimuli induce stable epigenetic alterations that maintain
inflammatory gene accessibility even after removal of the initial trigger.[16,17] Within this
framework, NF-κB functions not only as an inducible transcription factor but as an epigenetic
regulator that recruits chromatin-modifying enzymes, establishes transcriptional memory, and
sustains inflammatory signalling programs.
Emerging evidence suggests that nutraceutical polyphenols do not simply suppress inflammation
transiently; rather, they may reprogram inflammatory chromatin states, restoring regulatory
balance through coordinated modulation of DNA methylation, histone acetylation, and non-coding
RNA networks.[14,18]
This review therefore examines chronic inflammatory diseases through the lens of the NF-κB–
epigenetic switch, positioning dietary polyphenols as potential agents in nutraceutical therapy
capable of reversing pathological inflammatory memory.
Nf-κb signalling in inflammation
Nuclear factor κB (NF-κB) was first identified in B cells in 1986, where it bound to the enhancer
element of the κ-IgG chain gene.[19] Since then, NF-κB has been recognized as a family of
inducible transcription factors expressed in nearly all cell types, regulating apoptosis, cell cycle
progression, immune responses, and inflammation.[20,21] The NF-κB family consists of five
members—NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel—which form homo- or
heterodimers that bind to κB enhancer DNA elements to regulate transcription.[22,23] In resting
cells, NF-κB dimers are sequestered in the cytoplasm by inhibitory proteins of the IκB family, of
which IκBα being the most studied. Precursor proteins p105 and p100 also act as IκB-like
inhibitors due to their C-terminal ankyrin repeat domains.[24–26]
NF-κB is activated in response to inflammatory stimuli such as cytokines, oxidative stress,
microbial products, and metabolic imbalance. Activation commonly occurs through Toll-like
receptor signalling and cytokine receptor engagement, leading to phosphorylation and degradation
of inhibitory IκB proteins. This process allows NF-κB dimers to translocate into the nucleus and
initiate transcription of pro-inflammatory genes.[27,28] Key NF-κB-regulated mediators include
Tumour necrosis factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-1β (IL-1β), Cyclooxygenase-
2 (COX-2), and Inducible nitric oxide synthase (iNOS).[29]
Sustained NF-κB activation promotes chronic inflammation, oxidative damage, fibrosis, and
metabolic dysfunction; therefore, modulation of NF-κB signalling represents a critical therapeutic
target.[30] The NF-κB pathways that cells use to transmit signals to the nucleus include two primary
mechanisms, known as the canonical and non-canonical NF-κB pathways, which, are
schematically outlined in Figure 1. These two pathways rely on completely different receptor
systems, proteins, and timelines to control gene expression. In the canonical pathway, ligands
(such as TNF-α, IL-1β, and LPS) bind to their respective receptors, activating the IKK kinase
complex. This complex phosphorylates IκB, triggering its degradation by the proteasome and
releasing the p65/p50 dimer. The dimer then rapidly translocate to the nucleus to activate pro-
inflammatory genes. This response is eventually terminated by the resynthesis of IκB and its
IκB=Inhibitor of nuclear factor kappa B; IKK=IκB kinase complex; IKKα=IκB kinase alpha subunit; NIK=NF-κB-
inducing kinase; TNFα, IL-1β, LPS, CD40L, BAFF, and Ltβ are ligands.
Figure 1. Schematic illustration of the canonical (left) and non-canonical (right) NF-κB pathways. Ligand
binding to their respective receptors activates upstream kinases, leading to the degradation or processing
of cytoplasmic inhibitors, followed by the release of the active nuclear factor dimers. The dimers then
translocate to the nucleus and bind to specific DNA enhancer elements to regulate
target gene transcription.
subsequent rebinding to nuclear factors, p65 and p50. In contrast, in the non-canonical pathway,
ligands (such as CD40L, BAFF, and LTβ) activate a distinct cascade mediated by NF-κB-inducing
kinase (NIK) and its subunit, IKKα. This induces partial proteasomal processing of the precursor
p100 into p52, generating the active p52/RelB dimer to drive a delayed, sustained transcriptional
response.
Epigenetic regulation of nf-κb activity
Epigenetic mechanisms determine the magnitude and duration of NF-κB-mediated transcription.
Immune tolerance is a highly regulated state and involves diverse mechanisms. Central to the
induction of tolerance is the targeted modulation of T-cell activities of both effector and regulatory
T-cell activities, in which transcription factors play a significant role. Members of the NF-κB
family of transcription factors are critically involved in diverse T-cell responses and are regulated
by multiple mechanisms that maintain immune tolerance and T-cell homeostasis.[30,31]
NF-κB, as a transcription factor, has been extensively studied in recent decades, and the molecular
mechanisms that regulate NF-κB activities have been well documented. However, recent studies
have revealed exciting new roles for NF-κB; in addition to its transcriptional activity, NF-κB can
also activate diverse epigenetic mechanisms that mediate extensive chromatin remodelling of
target genes to regulate T-cell activities.[32,33]
Recent discoveries have expanded our understanding of NFkB factor. Beyond its classical role in
gene transcription, NF-κB has now been shown to influence epigenetic processes (Figure 2).
Through these mechanisms, NF-κB exerts broad control over T-cell function, revealing new
dimensions of its role in immune regulation.[33,34]
DNMT=DNA methyl transferase; EGCG=Epigallocatechin-3-gallate; HAT=Histone acetyltransferase;
HDAC=Histone deacelylase; SIRT1=Sirtuin 1 (or Silent Information Regulator 1)
Figure 2: Modulation of DNMTs, HATs, and HDACs by polyphenols in immune regulation. Polyphenols
suppress inflammation and help restore immune homeostasis through multiple epigenetic mechanisms by
inhibiting DNMTs, thereby promoting the production of anti-inflammatory mediators through
hypomethylation of genes involved; by inhibiting HATs, thereby influencing inflammatory signalling
pathways through modulating chromatin structure; and by activating HDACs and SIRT1, thereby
reducing the production of pro-inflammatory mediators through silencing specific genes.
DNA methylation
DNA methyltransferases (DNMTs) regulate the methylation of promoter regions of inflammatory
genes. Hypomethylation enhances transcription of cytokine genes, whereas hypermethylation
suppresses anti-inflammatory mediators.[35]
DNA methylation involves the covalent addition of a methyl group to the 5’ carbon of cytosine
residues within CpG dinucleotides, catalysed by a family of DNA methyltransferases (DNMT1,
DNMT3A, DNMT3B). This modification typically acts as a transcriptional repressor, silencing
gene expression by hindering transcription factor binding and recruiting methyl-CpG binding
proteins.[36,37] In chronic inflammatory diseases, promoter hypomethylation enhances transcription
of cytokine genes (e.g., TNF, IL6, CXCL8), whereas hypermethylation suppresses anti-
inflammatory mediators such as suppressors of cytokine signalling (SOCS) and PPAR-γ. Aberrant
DNA methylation patterns have been identified as biomarkers and functional contributors in
atherosclerosis, type 2 diabetes, chronic obstructive pulmonary disease (COPD), and rheumatoid
arthritis.[38,39]
Resveratrol has been shown to increase CpG methylation at the promoters of pro-inflammatory
cytokine genes (IL-1, IL-6, TNF-α, IFN-γ) while decreasing methylation at the IL-10 gene
promoter in the arterial intima of diabetic rats, correlating with reduced systemic inflammation and
endothelial protection.[40–42] Epigallocatechin gallate, (EGCG) a natural antioxidant compound
found mainly in green tea inhibits DNMT activity and has been shown to reactivate methylation-
silenced genes in cancer cell lines, some of which are negative regulators of NF-κB.[43,44] Curcumin
modulates DNMT function in models of diabetic retinopathy and colon cancer, contributing to
epigenetic reprogramming of inflammatory and tumour suppressor gene networks. Consumption
of cocoa flavanols has been shown to reduce global DNA methylation in peripheral leukocytes in
a randomized trial, with implications for cardiovascular inflammatory risk.[45–47]
Histone modifications
Histone acetylation promotes chromatin relaxation and transcriptional activation. Histone
acetyltransferases enhance NF-κB activity, whereas histone deacetylases (HDACs) suppress
inflammatory gene expression.[48]
HAT inhibition is the most widely reported epigenetic mechanism through which dietary
polyphenols suppress NF-κB. The HATs p300 and CBP function as transcriptional co-activators
for the p65 subunit: when recruited to NF-κB target gene promoters, they acetylate both histone
H3/H4 tails and the p65 subunit itself at K310, amplifying transcriptional output. Several
polyphenols directly inhibit p300/CBP acetyltransferase activity, thereby reducing p65 acetylation
and chromatin remodelling at inflammatory gene promoters.[14,49,50]
Curcumin is among the most potent dietary HAT inhibitors described to date. It inhibits p300
acetyltransferase activity in vitro with an IC50 (half maximal inhibitory concentration) in the
micromolar range and has been shown to reduce p65 acetylation and NF-κB transcriptional activity
in multiple cell models, including human monocytes and synovial fibroblasts. In THP-1
monocytes under high-glucose conditions, curcumin significantly reduces HAT activity and p300
protein levels while simultaneously inducing HDAC2 expression, resulting in decreased
production of IL-6 and TNF-α.[51,52]
EGCG, the predominant catechin in green tea, likewise potently inhibits p300/CBP HAT activity.
Choi and colleagues demonstrated that EGCG-mediated HAT inhibition led to p65 hypoacetylation
and suppressed TNF-α-induced expression of IL-6, COX-2, and iNOS in multiple cell types.
Similarly, quercetin has been shown to suppress p300 activity in breast cancer and endothelial
cells, reducing p300-mediated acetylation of the p65 subunit and downstream angiogenic and
inflammatory gene expression.[53,54]
HDAC activation and SIRT1-mediated deacetylation
In parallel with HAT inhibition, many polyphenols promote the deacetylation of p65 and
inflammatory gene histones by activating HDACs, particularly the NAD+-dependent deacetylase
SIRT1. SIRT1 occupies a privileged position in NF-κB regulation: it directly deacetylates p65 at
K310, the key activating acetylation site, and has been shown to inhibit NF-κB-mediated
transcription and reduce inflammatory cytokine production in macrophages and other immune
cells.[55,56]
Resveratrol is the archetypal SIRT1-activating polyphenol. It directly activates SIRT1 through an
allosteric mechanism, enhancing its catalytic activity towards p65 and other substrates. Pan and
colleagues demonstrated that resveratrol-induced SIRT1 activation suppressed TNF-α-induced
NF-κB and p38 MAPK signalling in human umbilical vein endothelial cells (HUVECs), protecting
against endothelial inflammation.[57] In a randomized controlled trial in type 2 diabetes patients,
resveratrol supplementation over six months significantly increased SIRT1 expression in
peripheral blood mononuclear cells, correlated with reduced H3K56 acetylation and decreased NF-
κB-dependent inflammatory gene expression.[58–62]
Genistein, the soy isoflavone, similarly increases SIRT1 expression, leading to downstream
inhibition of NF-κB p65 and reduction of IL-1β levels in experimental models of diabetes.[63,64]
Combined treatment with luteolin and fisetin has been shown to synergistically activate SIRT1
while suppressing HAT activity, providing additive anti-inflammatory effects in THP-1
monocytes. The convergence of HAT inhibition and HDAC/SIRT1 activation by polyphenols—
operating in concert to reduce p65 acetylation and NF-κB activity—represents a robust and
potentially synergistic therapeutic strategy.[65,66]
Non-coding RNA regulation
MicroRNAs such as miR-146a and miR-155 modulate NF-κB signalling by targeting pathway
components, thus providing an additional regulatory layer. Non-coding microRNAs (miRNAs)
regulate NF-κB signalling at multiple levels, by targeting upstream regulators (e.g., IκBα, IKK
subunits), the p65 subunit itself, and downstream effectors (Table 1). Several oncomiRs and
inflammation-associated miRNAs are themselves NF-κB transcriptional targets, creating
regulatory feedback loops. Dietary polyphenols are emerging as significant modulators of these
miRNA networks.[67]
Table 1. Dietary polyphenols: Epigenetic targets and effects on NF-κB signaling
Polyphenol
Dietary source
Epigenetic mechanism
Effect on NF-κB signalling
Resveratrol
Grapes, red wine
SIRT1 activation, DNMT
modulation
Deacetylates p65; inhibits NF-κB-
mediated transcription; reduces IL-6,
TNF-α
Curcumin
Turmeric
HAT inhibition,
HDAC/DNMT
modulation, miRNA
regulation
Reduces p65 acetylation; inhibits IκBα
phosphorylation; downregulates COX-
2, iNOS, TNF-α, IL-6
EGCG
Green tea
HAT inhibition, DNMT
inhibition, HDAC
activation
Hypoacetylates p65; suppresses NF-
κB-mediated IL-6, COX-2, iNOS
Quercetin
Onions,
broccoli,
blueberries
HAT inhibition
(p300/CBP)
Suppresses p300-mediated NF-κB
acetylation; blocks NF-κB binding to
pro-inflammatory gene promoters
Genistein
Soy, legumes
DNMT inhibition, HAT
activation, SIRT1
activation, miRNA
Increases SIRT1; reduces NF-κB and
IL-1β; modulates miRNA-155/SOCS1
Fisetin
Vegetables,
strawberries
HDAC activation, HAT
inhibition
Deacetylates p65; suppresses cytokine
release via NF-κB pathway
Luteolin
Parsley, celery
HDAC activation,
HAT/p300 inhibition
Deacetylates p65; decreases IL-6 and
TNF-α; activates SIRT1 (combined
with fisetin)
Epicatechin
Cocoa, red wine
HDAC modulation, HAT
inhibition
Prevents H3K9 acetylation and H3K4
dimethylation; reduces NF-κB
expression and TNF-α
Gallic acid
Tea, berries,
olive oil
HAT inhibition, HDAC
activation
Decreases HAT activity in TNF-α-
activated monocytes; attenuates
inflammatory response
Ellagic acid
Berries,
pomegranates
HAT inhibition, HDAC
activation
Reduces HAT and increases HDAC
activity in monocytic cells
Genistein regulates miRNA-155, a key pro-inflammatory miRNA that normally suppresses
Suppressor of Cytokine Signalling 1 (SOCS1), a negative regulator of the NF-κB pathway. By
upregulating SOCS1 through miRNA-155 suppression, genistein inhibits NF-κB-mediated
inflammation in endothelial cells exposed to oxidized LDL.[68,69] Curcumin has been shown to alter
miRNA expression profiles in pancreatic cancer cells, affecting pathways that regulate NF-κB
activity. Resveratrol and its analogue pterostilbene modulate miRNA-mediated regulation of
SIRT1 and DNMT expression in prostate cancer models, with anti-inflammatory
consequences.[70,71]
Disease-specific implications
Cardiovascular disease and atherosclerosis
NF-κB-driven endothelial inflammation is a central event in atherogenesis, promoting expression
of adhesion molecules, monocyte recruitment, and smooth muscle cell proliferation. Resveratrol,
through SIRT1-mediated p65 deacetylation, has been shown to suppress TNF-α-induced NF-κB
activation in HUVECs, with protective effects on endothelial function.[72–75] Genistein modulates
the miRNA-155/SOCS1/NF-κB axis to reduce oxidized LDL-induced endothelial
inflammation.[76,77] Cocoa epicatechin consumption reduces DNA methylation in leukocytes of
individuals with cardiovascular risk factors in a clinical RCT. These findings collectively support
a role for dietary polyphenols as epigenetic cardioprotective agents operating through NF-κB
inhibition.[78,79]
Type 2 diabetes and metabolic syndrome
Chronic low-grade NF-κB-driven inflammation in adipose tissue, liver, and immune cells
contributes fundamentally to insulin resistance and the progression of type 2 diabetes. Curcumin,
EGCG, fisetin, and luteolin have each been shown to suppress NF-κB-dependent cytokine
production in monocytes under high-glucose conditions by inhibiting HAT activity and activating
HDACs. In a clinical randomized controlled trial resveratrol supplementation in type 2 diabetes
patients increased SIRT1 expression and reduced NF-κB-associated histone acetylation marks over
six months, suggesting clinically relevant epigenetic anti-inflammatory effects. Genistein similarly
increases SIRT1 and reduces NF-κB activity in diabetic animal models.[80,81]
Rheumatoid arthritis and inflammatory joint disease
Synovial NF-κB hyperactivation drives the production of IL-6, TNF-α, matrix metalloproteinases,
and RANKL, mediating cartilage and bone destruction in rheumatoid arthritis (RA). Curcumin has
been shown to reduce histone H3 acetylation at the IL-6 promoter in RA synovial fibroblasts by
inhibiting HAT activity, thereby decreasing IL-6 expression. SIRT1 has been identified as a key
epigenetic suppressor of NF-κB in RA, and resveratrol's activation of SIRT1-mediated inhibition
of the RANKL pathway represents a potential therapeutic approach. EGCG has shown similar
epigenetic anti-NF-κB effects in relevant cell models.[82,83]
Cancer
Constitutive NF-κB activation in tumour cells and the tumour microenvironment promotes
survival, proliferation, invasion, and immune evasion. The epigenetic anti-NF-κB activities of
polyphenols are relevant to oncology in several ways. EGCG inhibits DNMT activity, potentially
reactivating epigenetically silenced tumour suppressor genes that act as negative regulators of NF-
κB. Curcumin and resveratrol modulate HDAC and SIRT1 activity in cancer cell models,
suppressing NF-κB-driven survival signals. Genistein reverses hypermethylation of tumour
suppressor genes and modulates miRNA networks that regulate NF-κB in prostate and other
cancers.[84–86]
Neurodegenerative Diseases
Neuroinflammation driven by microglial NF-κB activation is a key pathological feature of
Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions. Curcumin,
resveratrol, quercetin, and luteolin have all demonstrated anti-neuroinflammatory properties in
cellular and animal models, at least in part through epigenetic suppression of NF-κB. Curcumin
modulates Nrf-2 signalling and antioxidant gene expression through epigenetic mechanisms,
indirectly reducing oxidative-stress-driven NF-κB activation in neural tissues.[87–89]
Translational challenges as therapeutics
Bioavailability and metabolism
A fundamental challenge in translating the epigenetic NF-κB- modulating effects of polyphenols
into clinical benefit arises from their generally poor bioavailability. Most polyphenols undergo
extensive metabolism, rapid conjugation (glucuronidation, sulfation, methylation), and microbial
transformation in the gut, resulting in low systemic bioavailability of the parent compound. The
bioactive metabolites that reach target tissues may differ substantially in potency and mechanism
from the parent polyphenol. For example, resveratrol undergoes rapid metabolism to piceid and
other conjugates in vivo, which may retain some SIRT1-activating activity but at generally lower
potency.[90–94]
Strategies to enhance polyphenol bioavailability under investigation include nanoparticle
encapsulation, liposomal formulations, co-administration with bioavailability enhancers (e.g.,
piperine with curcumin), and structural modifications to produce more bioavailable analogues
(e.g., pterostilbene as a resveratrol analogue with greater lipophilicity and metabolic stability).
Dosing and clinical evidence
The concentrations of polyphenols required to produce epigenetic effects in cell culture models
frequently exceed those achievable through dietary intake alone, raising questions about the
clinical relevance of observed in vitro effects. Randomized controlled trials are limited in number
and often confounded by issues of standardization, compliance, and variability in polyphenol
metabolism between individuals. The two human trials reviewed here (resveratrol in type 2
diabetes and cocoa flavanols in cardiovascular risk) demonstrate proof-of-concept for clinically
measurable epigenetic effects, but larger, more rigorously designed trials are needed.[95,96]
Polyphenol interactions and dietary context
The human diet contains combinations of hundreds to thousands of polyphenols; however, the
synergistic or antagonistic interactions between them remain poorly understood. The observed
additive anti-inflammatory effects of fisetin-luteolin combination and the complementary
mechanisms of resveratrol (SIRT1 activation) and EGCG (HAT inhibition) suggest that
Figure 3. Clinical challenges of polyphenols. Polyphenols show limited clinical translation due to poor
bioavailability, metabolic transformation, and rapid clearance. Delivery strategies (nanoparticles,
liposomes, piperine) improve uptake, but high in vitro doses, few human trials, and variable effects
highlight the need for more rigorous evidence.
co-administration or dietary patterns rich in diverse polyphenols may produce greater epigenetic
NF-κB inhibition than individual compounds alone (Figure 3). Future research should examine
polyphenol combinations and dietary pattern effects on NF-κB epigenetics.[69,97]
Epigenome-wide effects and off-target risks
Epigenetic modifications are, by nature, pleiotropic: interventions that modulate HAT, HDAC,
DNMT, or miRNA activity will affect the expression of thousands of genes, beyond those regulated
by NF-κB. The long-term consequences of dietary epigenetic modulation by polyphenols,
including potential effects on immune tolerance, cell differentiation, and genomic stability, are not
well characterized. High-dose polyphenol supplementation has been associated with pro-oxidative
effects and, in the case of isoflavones, potential hormonal effects, underscoring the need for careful
dose-response characterization and long-term safety monitoring in clinical trials.[98,99]
Conclusion
Dietary polyphenols have been shown to exert anti-inflammatory effects through the epigenetic
regulation of NF-κB activity. This review discusses how polyphenols such as resveratrol,
curcumin, EGCG, quercetin, genistein, fisetin, luteolin, and epicatechin engage multiple
epigenetic targets through HAT inhibition, HDAC/SIRT1 activation, DNA methylation
modulation, and miRNA regulation, to reduce p65 acetylation, suppress NF-κB transcriptional
activity, and decrease production of pro-inflammatory cytokines and mediators.
The interplay of HAT inhibition and SIRT1-mediated p65 deacetylation emerges as an epigenetic
axis through which polyphenols modulate NF-κB. Different classes of polyphenols can work
together, suggesting that a variety of dietary sources may collectively provide epigenetic anti-
inflammatory protection, supporting the use of diverse diets and polyphenol combinations in
therapeutic strategies.
Despite promising preclinical evidence and emerging clinical data, significant challenges remain
in translating polyphenol epigenetics into clinical practice. The issues of bioavailability, effective
dosing, the complexity of polyphenol metabolism, interindividual variability, and the potential for
off-target epigenomic effects must be addressed through rigorous clinical trial design and
mechanistic research. However, the epigenetic modulation of NF-κB by dietary polyphenols is an
emerging and rapidly advancing area of research that holds significant promise for the prevention
and management of chronic inflammatory diseases.
Financial support and sponsorship
Nil.
Conflict of interest
There are no conflicts of interest.
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