ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 3, pp. 432-447 © Pleiades Publishing, Ltd., 2026.
432
REVIEW
Epigallocatechin Gallate as an Anti-Fibrotic Agent
Yury S. Tarahovsky
1,a
*, Sergey G. Gaidin
2
, and Yury A. Kim
2
1
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences,
142290 Pushchino, Moscow Region, Russia
2
Institute of Cell Biophysics, Pushchino Scientific Center for Biological Research, Russian Academy of Sciences,
142290 Pushchino, Moscow Region, Russia
a
e-mail: tarahov@rambler.ru
Received October 21, 2025
Revised February 18, 2026
Accepted February 19, 2026
Abstract— Epigallocatechin gallate (EGCG), a major polyphenolic compound in green tea, exhibits preventive
and therapeutic effects in many fibrotic diseases. Tissue fibrosis is characterized by excessive deposition of
collagen fibrils in the extracellular matrix, primarily due to dysregulation of cellular signaling pathways.
However, we have previously demonstrated that EGCG directly inhibits the formation of collagen fibrils from
collagen monomers under in vitro experimental conditions that excluded involvement of cellular signaling
systems. This review explores the antifibrotic action of EGCG, which may occur through (i) its influence
on cellular signaling and (ii) direct binding to collagen monomers, leading to the inhibition of pathological
fibrillogenesis, as well as discuss the prospects for targeting the collagen assembly process.
DOI: 10.1134/S0006297925603715
Keywords: collagen, fibrosis, polyphenols, flavonoids, catechin, epigallocatechin gallate
* To whom correspondence should be addressed.
INTRODUCTION
Polyphenolic compounds found in plant-based
foods are among the most important functional com-
ponents of human diet [1, 2]. Special attention has
been given to flavonoids – a class of natural poly-
phenolic compounds abundant in fruits, vegetables,
grains, and tea. Flavonoids, widely consumed through
everyday foods, exhibit antioxidant, anti-inflamma-
tory, anticancer, antibacterial, and neuroprotective
properties, thus reducing the risk of various diseases
[3-5]. Some flavonoids possess hepatoprotective prop-
erties and have been also investigated as potential
treatments for central nervous system disorders, such
as the Alzheimer’s and Parkinson’s diseases, drug ad-
diction, and stroke, as well as for their preventive
role in ischemic heart disease [6]. Clinical studies
have demonstrated that fruits rich in flavonoids can
help prevent cancer by affecting signaling pathways
involved in angiogenesis and carcinogenesis [7]. Fla-
vonoids are also clinically effective in preventing
type 2 diabetes [8].
In this review, we discuss potential mechanisms
underlying the preventive action of epigallocate-
chin-3-gallate (EGCG), one of the main catechins in
tea, in fibrotic diseases of various organs. Using lit-
erature data and findings from our own research, we
propose a hypothesis for the EGCG action mechanism.
FIBROSIS AND HEALTH
Fibrosis, which accounts for nearly 50% of glob-
al mortality, results from uncontrolled inflammatory
processes characterized by excessive deposition of the
extracellular matrix (ECM), ultimately leading to or-
gan dysfunction [9]. Although the primary causes of
fibrosis may vary and are not yet fully understood,
these diseases share a common pathological hallmark:
the progressive accumulation of fibrous tissue rich in
fibrillar proteins (primarily collagen) in affected or-
gans, culminating in organ failure [10-12].
For example, excessive accumulation of collagen
fibrils at the site of myocardial injury is known as
cardiac fibrosis [13]. Chronic activation of wound
healing responses causes fibrosis characterized by
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disproportionate ECM formation as a result of sus-
tained inflammation, with activated fibroblasts play-
ing a key role in this process [14, 15]. Initially, fi-
brosis may serve as a compensatory mechanism in
response to prolonged healing, but persistent repar-
ative fibrosis can eventually lead to complications
by impairing heart function and increasing tissue
rigidity. Thus, the formation and expansion of scar
tissue can compromise heart function [16], as dam-
aged cardiomyocytes are replaced by non-contractile
fibrous scar tissue, which can lead to heart failure
due to the limited ability of the heart muscle to con-
tract [17]. Although replacement of damaged tissues
by collagen-rich fibrous scar tissue is a part of body’s
natural response aimed to expedite the recovery after
injury, it often leads to cardiac muscle dysfunction
[18, 19]. After myocardial infarction, when coronary
artery blockage causes extensive death of heart mus-
cle tissue, this process, known as cardiac remodeling,
becomes particularly pronounced.
During cardiac remodeling, necrotic tissue is re-
placed by the ECM, while the remaining viable car-
diomyocytes undergo hypertrophic growth. The ECM
is produced primarily by fibroblasts and includes col-
lagen, proteoglycans, fibronectin, tenascin C, laminins,
and elastin [15, 20]. The heart contains various types
of fibrillar collagen, each with unique physical and
chemical properties. Type I collagen, which consti-
tutes ~85% of total cardiac collagen, forms thick fi-
bers that provide strength. In contrast, type III col-
lagen forms flexible, thin fibers that ensure tissue
elasticity [21]. Cardiac remodeling, i.e., replacement
of damaged tissue with fibrous material, results in
the loss of contractile cardiac muscle mass [22].
Chronic liver inflammation is another example
of pathology associated with fibrosis. Hepatic fibro-
genesis, one of the leading causes of morbidity and
mortality worldwide, can be initiated by viral, chemi-
cal, or metabolic agents [15]. A key event accelerating
liver fibrosis is the activation of collagen-producing
hepatic stellate cells (HSCs) [23]. Over time, fibrosis
can spread throughout the entire liver, increasing the
risk of morbidity and mortality, especially in the con-
text of age-related disorders [24].
Nonalcoholic fatty liver disease is characterized
by the inflammation and tissue damage, as well as
excessive lipid accumulation that damages hepato-
cytes and can lead to fibrosis, a pathological process
in which normal liver parenchyma is progressively
replaced by fibrous connective tissue. This remodel-
ing impairs liver function and eventually progresses
to cirrhosis, a condition marked by a significantly re-
duced liver performance [25, 26]. Activated HSCs are
the primary effector cells driving liver fibrogenesis
[27] by producing excessive amounts of ECM com-
ponents [23]. The ECM is a complex network formed
by collagens, elastin, glycoproteins, and proteoglycans
[28-30]. Since collagen is the main ECM component, it
plays a vital role in the development and etiology of
chronic liver diseases [31].
THE EFFECT OF EGCG ON FIBROSIS
EGCG is widely recognized for its ability to pre-
vent inflammatory diseases accompanied by tissue fi-
brosis and damage to many organs. The most prom-
ising therapeutic strategies for treating fibrosis have
been focused on preserving collagen homeostasis,
specifically, by regulating its formation, deposition,
and degradation [32]. EGCG has demonstrated signif-
icant therapeutic potential against fibrosis in various
organs.
Many researchers believe that the modulation of
cellular signaling pathways is central to the EGCG’s
mechanism of action. For example, in liver fibrosis,
EGCG exhibits antifibrotic, antioxidant, and anti-in-
flammatory effects by suppressing the expression of
cellular signaling components, such as TNF-α, IL-1β,
TGF-β, MMP-2, MMP-9, α-SMA, and COL1A1 [33-36],
and by inhibiting pro-inflammatory (IL-5, TNF-α, IFNγ,
IL-4, IL-1B, IL-6) and stress (p53, p38, MAPK, XBP1)
signaling pathways [37]. EGCG treatment has been as-
sociated with reduced levels of the lipid peroxidation
marker malondialdehyde, as well as with decreased
expression of NF-κB, TNF-α, IL-1β, IL-6, IL-10, TGF-β,
and α-SMA [38, 39].
In renal fibrosis, EGCG promotes the transdif-
ferentiation of macrophages into myofibroblasts via
the TGF-β/Smad3 and JAK/STAT signaling pathways
[40]. In cardiac fibrosis, EGCG reduces atherosclero-
sis-associated cardiovascular toxicity by suppressing
mitochondrial DNA sensitivity regulated by the TBK1/
cGAS/STING and NLRP3 signaling pathways [41] and
prevents inflammation and cell death by reducing the
production of reactive oxygen species (ROS) and Bax
expression, while upregulating Bcl-2 expression [42].
Additionally, it has been found that EGCG downreg-
ulates collagen expression by inhibiting the TGF-β/
Smad3 and LOX signaling pathways [43], activates
autophagy, modulates the AMPK/mTOR pathway, sup-
presses the TGF-β/MMP pathway [44], and reduces the
expression of TGF-β, JNK, p-JNK, and TIMP-1, while
activating the MMP-9 pathway [45].
In summary, EGCG is one of the most effective
agents for preventing inflammation and fibrosis, as
evidenced by the reduced levels of pro-inflammatory
markers and suppression of oxidative stress, collagen
production, and cell apoptosis [23, 46-48].
As illustrated in Fig. 1, EGCG inhibits key compo-
nents of cellular signaling, including NFκB and STAT
transcription factors, as well as the protein kinase
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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 3 2026
Fig. 1. The effects of EGCG on cell proliferation signaling
pathways. The diagram shows molecules frequently men-
tioned in the studies of EGCG’s effects on fibrosis; red cir-
cles denote the inhibitory effect of EGCG on the signaling
pathway components (see the text for details).
mTOR, particularly in cancer cells [49]; however, this
effect in primary cells has been studied insufficient-
ly. Under certain conditions, EGCG acts as an antiox-
idant and suppresses ROS production, which will be
discussed in more detail in the following sections of
this review. As an antioxidant, EGCG acts through the
NFκB and STAT transcription factors and exerts its an-
ti-inflammatory effect via suppressing the expression
of pro-inflammatory cytokines TNF-α, IL-1, IL-6, and
IL-8. By acting through the TGF-β, JNK, and mTOR sig-
naling pathways, EGCG suppresses activation of HSCs
and fibroblasts, thus downregulating the activity of
NFκB and STAT, which inhibits the production of col-
lagen, reduces fibrotic tissue formation, and prevents
subsequent cell apoptosis by inhibiting the formation
of mitochondrial pores by the Bax protein [50, 51].
ANTI- AND PRO-OXIDANT ACTIVITY OF EGCG
EGCG is widely recognized as a potent antioxidant,
whose protective effect is attributed to the ability to
upregulate the expression of catalase, superoxide dis-
mutase, and glutathione peroxidase, thus preserving
the mitochondrial membrane integrity [52]. However,
evidence also suggests that catechins can exhibit the
pro-oxidant properties and increase ROS levels. While
catechins typically prevent oxidation by scavenging
free radicals, they can promote ROS generation and
exhibit the pro-oxidant activity [53].
The biological activity of EGCG largely depends
on its concentration, with the antioxidant prop-
erties observed only at very low concentrations
(0.1-0.01 µM) and the pro-oxidant activity dominat-
ing at higher concentrations (1-100 µM), as has been
shown in healthy human lymphocytes [54]. A study in
hepatocytes reported no detectable toxicity of EGCG
at concentrations ≤1 µM, although such toxicity was
observed at concentrations ≥10 µM [55]. These find-
ings demonstrated the dual nature of EGCG and its
ability to exhibit both anti- and pro-oxidant proper-
ties. Remarkably, even at higher concentrations asso-
ciated with increased ROS production, EGCG can still
produce beneficial therapeutic outcomes [56]. For
example, EGCG at concentrations of 50-100 µg/mL
(1-2 µM) demonstrated antifibrotic, antiangiogenic,
and pro-apoptotic effects, contributing to the allevi-
ation of menopausal symptoms and fertility preser-
vation [57]. The pro-oxidant activity of EGCG, when
combined with other polyphenols exhibiting antioxi-
dant properties, may have advantages in therapeutic
applications [58].
The therapeutic effects of EGCG may arise from
its capacity to inhibit the proliferation of rapidly di-
viding cells, induce cell cycle arrest at the G
0
/G
1
phase,
initiate cell apoptosis, and suppress cell growth, as
has been extensively documented in cancer cells [59].
High ROS levels promote cell death, a phenomenon
observed in primary cells and even to a greater ex-
tent, in cancer cells, suggesting potential application
of EGCG and other flavonoids in anticancer chemo-
therapy [60, 61]. The strategies enhancing the pro-oxi-
dant action of EGCG can be used in both cancer ther-
apy [61] and treatment of injuries of healthy tissues
[62, 63]. One such approach involves generation of in-
creased ROS amounts through the formation of com-
plexes with metal ions (e.g., copper and iron), which
induces the production of hydrogen peroxide via the
Fenton reaction, thus amplifying the pro-oxidant and
cytotoxic effects and ultimately inhibiting cancer cell
proliferation. EGCG–Cu
2+
complexes at the concentra-
tions of 50-300 µM demonstrated a pronounced activ-
ity, with EGCG exhibiting the highest potency among
tea catechins [64].
It should be emphasized that the action of poly-
phenol–metal complexes is highly concentration-de-
pendent, a factor that remains investigated rather
insufficiently. For example, the EGCG–Zn
2+
complex
reduces ROS production, suppresses inflammatory
reactions, and promotes angiogenesis, thereby con-
tributing to a significant therapeutic effect in vari-
ous diseases [65-67]. Comparative protective effects
were observed for the EGCG–Mg
2+
and EGCG–Cu
2+
complexes [68, 69]. However, administration of high
doses of EGCG may induce significant damage, lead-
ing to hepatotoxicity and even lethal outcomes, due
to its pro-oxidant action [70].
To illustrate the dual (anti- and pro-oxidant),
concentration-dependent role of polyphenolic com-
pounds in modulating cell proliferation, the concept
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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 3 2026
Fig. 2. The “double-edged sword” principle in the antifibrotic action of EGCG in rapidly dividing cells (activated fibroblasts
or HSCs) explains the effects of low (a), moderate (b), and high (c) concentrations of EGCG on cell proliferation and viability.
of a “double-edged sword” has been proposed [71-73]
(Fig. 2). According to this hypothesis, very low EGCG
concentrations (Fig. 2a) are associated with high cy-
toplasmic ROS levels, resulting in the cytostatic effect.
At the same time, EGCG in very high concentrations
manifests the pro-oxidant properties, further increas-
ing the content of ROS levels in the cytoplasm and
inducing cytotoxicity (Fig. 2c). The lowest ROS levels
are observed at moderately high EGCG concentrations
(Fig. 2b).
The “double-edged sword” phenomenon has been
reported not only for EGCG [74] but also for other
natural polyphenolic antioxidants, such as curcumin
[75] and resveratrol [59, 76]. To date, this dual action
has been documented primarily in the studies of can-
cer cells. Whether a similar mechanism operates in
rapidly proliferating activated fibroblasts and HSCs,
i.e., the cells contributing to the collagen production
and its fibrotic deposition, remains to be determined.
THE EFFECT OF EGCG
ON THE COLLAGEN FIBRIL FORMATION
Collagen molecules, which can self-organize into
larger structures called collagen fibrils, are pro-
duced by cells from various organs. Collagen fibrils
are fundamental components of connective tissue
that are responsible for bearing much of the body’s
mechanical load. They often cluster into higher-or-
der structures, such as intervertebral discs, corneal
lamellae, and tendon bundles [77]. Their regenera-
tive potential, mechanical properties, and functions
depend on several factors related to the collagen ar-
chitecture, in particular, alignment of parallel fibers,
intermolecular cross-linking, and fibril packing densi-
ty [78]. The spontaneous assembly of collagen fibrils
from collagen monomers can be reproduced in vitro.
In acidic environments, fibrillar collagen isolated
from animal tissues dissociates into individual colla-
gen monomers. When exposed to neutral or weakly
alkaline conditions, these molecules reassemble into
bundles of fibrils with a characteristic cross-striation
that can be observed under an electron microscope
(Fig. 3a). As we have previously shown, EGCG inhib-
its the formation of collagen fibrils from collagen
monomers [79]. Thus, in the presence of EGCG, elec-
tron microscopy revealed only unstructured material
consisting of individual collagen molecules (Fig. 3b).
Turbidimetric analysis further confirmed the
EGCG’s ability to prevent the formation of collagen
fibrillar structures, as evidenced by a significant
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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 3 2026
Fig. 3. Transmission electron microscopy of typeI collagen fibrils. Cross-striated fibrils (a, control) and disordered collagen
monomer molecules in the presence of 1 µM EGCG (b) (see [79] for details).
reduction in the optical density when the collagen
solution was transferred from the acidic to neutral
environment (Fig. 4). These findings indicate that tea
catechins, like some other compounds, significant-
ly affect the formation of collagen fibrils [79-84].
The correlation of the data presented in vitro with
the in vivo experiments is noteworthy. For example,
in vitro EGCG inhibits fibril assembly, while catechin
accelerates this process [79]. Similarly, EGCG prevent-
ed the development of nonalcoholic steatohepatitis
and, accordingly, inhibited the formation of colla-
gen fibrils and the development of collagenosis in a
mouse model, whereas catechin failed to demonstrate
this protective effect [85].
We have previously demonstrated that many
polyphenolic compounds, including simple phenols
(phenol, pyrocatechol, resorcinol, and pyrogallol)
accelerate collagen fibrillogenesis [86]. Among flavo-
noids, kaempferol and flavone accelerate collagen
fibril formation, while quercetin and myricetin sup-
press it [80, 81], the effect correlating with the num-
ber of hydroxyl groups in the B-ring of these mol-
ecules [80]. Overall, most polyphenols examined in
our studies promoted collagen fibril formation and
only a few inhibited it. Although research in this
area is far from complete, EGCG likely demonstrates
the greatest activity against fibril formation among
the agents listed above. It is also well recognized for
its antifibrotic action. In recent years, particular at-
tention has been given to EGCG’s ability to promote
scarless wound healing, which is associated with
the downregulation of genes encoding TGF-β1, Col-I,
EPIGALLOCATECHIN GALLATE AS ANTI-FIBROTIC AGENT 437
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 3 2026
Fig. 4. Effect of green tea catechins on the optical density of collagen monomer solution during collagen fibril formation:
control (1); in the presence of 1 µM catechin (2); in the presence of 1 µM EGCG (3) (see [79] fordetails).
Col-III, α-SMA, and eNOS [87]. The antifibrotic activity
that supports scarless wound healing has also been
reported for quercetin and myricetin [88, 89], con-
sistent with their capacity to inhibit collagen fibril
formation.
THE EFFECT OF EGCG
ON PROTEIN–PROTEIN INTERACTIONS
The inhibitory effect of EGCG on collagen fibril
formation is not unique and has been observed with
other proteins as well. EGCG is known to modify
the structure of certain proteins and prevent fibril
formation [90]. This activity likely arises from the
EGCG’s ability to interact with polar and aromatic
residues through hydrogen bonds, π–π interactions,
and cation–π interactions, due to a greater number
of aromatic rings and hydroxyl groups in the EGCG
molecule compared to most flavonoids. As a result,
EGCG can effectively disrupt intra- and intermolecu-
lar interactions in protein aggregates [91].
For example, EGCG prevents the aggregation of
various amyloid-forming proteins, which is the cause
of amyloidosis [92]. Amyloidoses are a group of more
than 40 diseases characterized by the accumulation
of protein aggregates in human tissues. Aggregation
of amyloid proteins can contribute to neurodegener-
ative diseases, such as the Huntington’s disease, Par-
kinson’s disease, and Alzheimer’s disease [93].
Amyloid assembly results from the interaction of
protein filaments with the formation of β-sheet-rich
fibrillar structures [93]. Small peptides, such as am-
yloid-beta (Aβ) and islet amyloid polypeptide (IAPP),
can form toxic amyloid aggregates via both cross-as-
sembly and self-assembly. Typically, amyloid peptides
form stable heterodimers that serve as co-aggrega-
tion precursors. By reducing the number of β-sheets
in the peptides, EGCG inhibits oligomer forma-
tion [94, 95].
EGCG prevents the aggregation of multiple patho-
genic proteins, such as huntingtin, Aβ, and α-synucle-
in. EGCG inhibits the fibrillogenesis of these proteins,
reduces amyloid cytotoxicity, and promotes fibril re-
modeling into non-toxic amorphous structures both
in vitro and in vivo [93]. By blocking the formation
of bonds between Aβ
40
and Aβ
42
, EGCG effectively
prevented their co-dimerization, a key process in the
pathophysiology of Alzheimer’s disease [91]. EGCG
binds to Aβ
40
and Aβ
42
through hydrogen bonds, π–π
interactions, and cation–π interactions with polar and
aromatic residues on these peptides. By disrupting
long-range interactions, EGCG disaggregates mixed
Aβ
40
–Aβ
42
fibrils [91]. EGCG also inhibited the fibril-
logenesis of Aβ and α-synuclein, reducing their cellu-
lar toxicity [96]. Additionally, EGCG can suppress the
development of pathological processes characteristic
of Alzheimer’s disease by preventing tau protein ag-
gregation [97, 98].
The effect of EGCG on the NLRP3 inflammasome
further demonstrates its ability to modify protein–
protein interactions. The NLRP3 inflammasome re-
leases pro-inflammatory cytokines such as IL-1β/IL-18
in response to microbial infection and cell damage.
EGCG has a high affinity for the NLRP3 protein, thus
preventing inflammasome activation [99].
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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 3 2026
EGCG INTAKE DOSES
AND EGCG BODY CONTENT
The proposed optimal therapeutic dose of EGCG
(200 mg/kg body weight) has been shown to signifi-
cantly reduce the levels of the pro-inflammatory cy-
tokines TNF-α, IL-1β, and IL-18 [100]. Other studies
have indicated that the therapeutic effects of EGCG
can be observed even at lower doses (20-25 µg/kg
body weight) [34, 38, 101]. In cellular models, the
effective concentrations of EGCG were 1 µM [102],
0.1 µM, 10 µM [103], and 35 µg/mL [104]. Further-
more, local application of EGCG solutions (10-100 µM)
has exhibited the antifibrotic effects and promoted
wound healing [34, 105-107].
The bioavailability of EGCG consumed with food
is low [108]. Consequently, systemic EGCG concentra-
tions achieved through dietary intake are considerably
lower than those used in cell models or local appli-
cations. For example, consuming a single cup of tea
typically results in the plasma catechin concentration
of approximately 0.5 µM [109]. In another study, oral
administration of 1.5 mmol of EGCG in volunteers pro-
duced the peak blood content of this agent of 1.3 µM
within 2-3 h [110-115], followed by a slow elimination
at a rate of t
1/2-elim
= 5-5.5 h [110]. According to the
recommendations of the European Food Safety Au-
thority (EFSA), the daily intake of EGCG for an adult
is 90-300 mg (about 4 cups of tea per day) [116]. How-
ever, for therapeutic purposes, higher doses can be
safely achieved through pharmaceutical formulations,
such as capsules or tablets [116]. For example, a clini-
cal study showed that daily intake of 1600 mg of EGCG
for 4 weeks, which is equivalent to 16 cups of green
tea per day, was well-tolerated in healthy individuals
and can be considered safe [117]. Dietary intake of
EGCG up to 500 mg/kg per day for 13 weeks in rats
and dogs caused no adverse effects and was also de-
termined as safe. However, taking large doses of EGCG
on an empty stomach can cause gastrointestinal dis-
comfort and hepatic stress [118]. Very high doses of
EGCG (up to 2000 mg/kg) were lethal to rats [119].
EGCG TARGETS IN CELLS AND TISSUES
The data above suggest the existence of multiple
potential therapeutic pathways for EGCG, which can
act at various stages of fibrotic changes in damaged
tissues. EGCG can penetrate into the cytoplasm [120]
due to the inherent ability of flavonoids to interact
with the phospholipid bilayer of cell membranes
[121], a process that can be facilitated by the forma-
tion of complexes with transition metals, such as iron
[122-124]. Therefore, a few hours after administration
of fluorescently labeled EGCG, its presence can be de-
tected in the cytoplasm, cellular compartments, and
the nucleus [125], suggesting the EGCG’s ability to
directly affect various intracellular processes. These
include modulation of gene expression through in-
teraction with DNA and RNA [126, 127], modulation
of intracellular signaling cascades through acting on
lipid rafts in membranes [128-131], and regulation of
processes related to the pro- and antioxidant activi-
ties of EGCG [120, 132, 133]. Remarkably, the effects
of EGCG on cell proliferation can also vary greatly
and even be the opposite. For example, in rapidly
dividing cells (e.g., tumor cells), EGCG inhibits the
activity of signaling cascades responsible for cell
division, such as those involving Akt, AMPK, and
NF-κB, leading to the cell cycle arrest, increased ROS
generation, and apoptosis [134-137], whereas in pri-
mary cells, EGCG activates AMPK-involving signaling
pathways that promote cell division and reduce ROS
production [138-140]. Among tea catechins, EGCG ex-
hibits the strongest capacity to influence intracellular
processes, which implies its significant potential for
medical applications [141].
Inflammatory processes lead to sustained tis-
sue damage in various organs, accompanied by cell
apoptosis and lipid peroxidation capable of trigger-
ing the activation of cardiac fibroblasts and HSCs.
Once activated, these cells increase the production of
proteins involved in the fibrotic deposition, includ-
ing collagen monomers which assemble in collagen
fibrils and contribute to the development of tissue
fibrosis as a result of ECM deposition. According to
our proposed scheme (Fig. 5), EGCG can intervene
at various stages of fibrotic changes. First, it targets
cells at the site of inflammation, exerting either cy-
tostatic or cytotoxic effect, depending on the concen-
tration and conditions, thereby inhibiting the activa-
tion of fibroblasts or HSCs (Fig. 5a). Second, EGCG
can also affect activated fibroblasts and HSCs and
suppress collagen monomer synthesis by these cells
(Fig. 5b). Finally, we propose a new mechanism for
the EGCG’s antifibrotic action. According to our find-
ings, EGCG inhibits the formation of collagen fibrils
by interacting with collagen monomers (Fig. 5c). This
effect increases with the increase in the EGCG con-
centration [79] and does not weaken or reverse, un-
like effects mediated by the anti- and pro-oxidant ac-
tivities.
It should be noted that the cellular effects of
EGCG strongly depend on the mode of application
and concentration of this agent. Despite numerous
published reports on the ECGC activity, most these
studies have not measured its concentration in the
blood, nor have they performed continuous monitor-
ing of this parameter. This omission is particularly
critical for oral administration, given EGCG’s low bio-
availability.
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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 3 2026
Fig. 5. Possible EGCG targets in the treatment of tissue fibrosis in cardiac muscle and liver. EGCG prevents the activation
of fibroblasts and HSCs (a), inhibits the secretion of proteins (mostly, collagen) by cells (b), and suppresses collagen fibril
formation and ECM deposition (c).
PROSPECTS FOR THE USE OF EGCG
IN PREVENTING FIBROTIC DISEASES
Many polyphenolic compounds, including EGCG,
have low solubility and bioavailability, which signifi-
cantly limits their therapeutic applications. Moreover,
the concentrations of these substances required to
achieve a therapeutic effect can sometimes have ad-
verse effects on healthy organs. Therefore, approach-
es are being developed to locally increase the concen-
tration of polyphenolic compounds directly at the site
of therapeutic intervention.
One of the most notable examples of the use of
the EGCG’s antifibrotic activity is the development
of new EGCG-enriched materials designed to prevent
keloid scar formation [62, 106, 142]. Even a simple
local injection of the preparation into the damaged
area produced significant anti-scar effect due to the
increased local EGCG concentration [87, 106]. In an
experimental scar formation model (healing of rab-
bit ears after injury), injection of 1 mg of EGCG has
a markedly greater healing and anti-scar effect com-
pared to injection of 0.5 mg of EGCG under the same
conditions, indicating a clear dose-dependent rela-
tionship [87].
Currently, several strategies have been developed
to sustain elevated levels of EGCG in the damaged
area. These include encapsulation of Cu
2+
–EGCG com-
plexes in a hydrogel to promote the healing of severe
burn wounds without scarring. This approach exem-
plifies successful exploitation of EGCG’s pro-oxidant
properties when complexed with metal ions [62, 63].
Another example is creation of nanosized coacervates
containing fibroblast growth factor and attached
EGCG–polylysine complex, which effectively prevent-
ed scar formation by achieving high local EGCG con-
centrations in the damaged area [143].
In these and similar studies, the observed ther-
apeutic effects of EGCG have been mostly attributed
to the EGCG’s ability to scavenge ROS from tissues
or to modulate cell signaling, thereby suppressing
inflammation and activating angiogenesis during
wound healing [62, 143-145]. We propose that the
EGCG’s ability to prevent fibrosis and promote scar-
less wound healing may result not only from its
effect on cellular signaling but also from the di-
rect interaction with collagen monomers, which
blocks collagen fibril formation. Our research in-
dicates (Fig. 4) that screening for potent inhibitors
of collagen fibrillogenesis among polyphenol-based
compounds or their derivatives can be carried out
in vitro by analyzing the dynamics of light scatter-
ing in collagen solutions during fibril formation [79].
This approach can substantially reduce research
time and costs and facilitate the development of new
drugs.
CONCLUSION
It is well established that EGCG can directly in-
teract with amyloid proteins and inhibit amyloid fi-
bril formation, thereby mitigating development of
neurological disorders, such as the Alzheimer’s dis-
ease. In contrast, most studies on the effect of EGCG
on the formation of collagen fibrils involved in fi-
brosis development have been focused on its antiox-
idant properties and ability to influence intracellular
signaling. The EGCG’s potential to directly influence
collagen fibrillogenesis, however, has often been
overlooked.
Our previous experiments have demonstrat-
ed that EGCG can effectively inhibit collagen fibril
formation in vitro, which excludes the involvement
TARAHOVSKY et al.440
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 3 2026
of cellular signaling systems and suggests the pos-
sibility of direct inhibitory effect of EGCG on the
formation of collagen fibrils in vivo. Understanding
the mechanisms by which EGCG modulates colla-
gen fibrillogenesis may open new prospects in the
development of drugs for the treatment of fibrotic
diseases.
Abbreviations
Aβ amyloid-beta
EGCG epigallocatechin-3-gallate
ECM extracellular matrix
HSC hepatic stellate cell
ROS reactive oxygen species
Contributions
Yu.S.T. developed the concept and wrote the text of
the article; S.G.G. participated in the described ex-
periments and edited the manuscript; Yu.A.K. devel-
oped the concept, supervised the study, and edited
the manuscript.
Funding
This study was supported by the Ministry of Science
and Higher Education of the Russian Federation as a
part of the State Assignment for the Institute of Cell
Biophysics, Russian Academy of Sciences (no. 075-
00612-26-00) and the State Assignment for the In-
stitute of Theoretical and Experimental Biophysics,
Russian Academy of Sciences (no. 075-00224-26-00).
Ethics approval and consent to participate
This work does not contain studies involving human
or animal subjects.
Conflict of interest
The authors of this work declare that they have no
conflicts of interest.
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