Esmaeili, 2025

Prévia do material em texto

REVIEW
Nanotechnology-driven EGCG: bridging antioxidant and therapeutic roles in 
metabolic and cancer pathways
Zahra Esmaeilia, Parisa Shavali Gilanib, Masood Khosravania, Maral Motamedia, Shokofeh Maleknejadc, Mahdi Adabia,d 
and Parisa Sadigharab
aDepartment of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; 
bDepartment of Environmental Health Engineering, Division of Food Safety and Hygiene, School of Public Health, Tehran University of Medical 
Sciences, Tehran, Iran; cDepartment of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, 
Ahvaz, Iran; dFood Microbiology Research Center, Tehran University of Medical Sciences, Tehran, Iran
ABSTRACT
Epigallocatechin-3-gallate (EGCG), the primary polyphenol in green tea, is renowned for its potent 
antioxidant properties. EGCG interacts with various cellular targets, inhibiting cancer cell proliferation 
through apoptosis and cell cycle arrest induction, while also modulating metabolic pathways. Studies 
have demonstrated its potential in addressing cancer development, obesity, and diabetes. Given the 
rising prevalence of metabolic diseases and cancers, EGCG is increasingly recognized as a promising 
therapeutic agent. This review provides a comprehensive overview of the latest findings on the effects 
of both free and nano-encapsulated EGCG on mechanisms involved in the management and prevention 
of hyperlipidemia, diabetes, and gastrointestinal (GI) cancers. The review highlights EGCG role in 
modulating key signaling pathways, enhancing bioavailability through nano-formulations, and its 
potential applications in clinical settings.
ARTICLE HISTORY
Received 28 October 2024 
Accepted 31 January 2025 
KEYWORDS
Epigallocatechin-3-gallate; 
gastrointestinal cancer; 
diabetes; hyperlipidemia; 
nano-encapsulation
1. Introduction
The rising prevalence of metabolic syndrome (MetS) and can-
cer has become a significant global health concern. These 
conditions involve multiple factors, including rising obesity 
rates, sedentary lifestyles, changes in cell signaling pathways, 
and various biological processes [1]. The use of medicinal 
plants and their key compounds is effective in controling 
these diseases and inhibiting the processes involved in carci-
nogenesis such as initiation, proliferation, and progression. 
Notably, EGCG, the most abundant catechin in green tea, has 
attracted significant attention due to its antioxidant properties 
and its capability as an anti-tumorigenic and anti- 
inflammatory compound [2]. Additionally, EGCG offers 
a comprehensive approach to addressing hyperlipidemia and 
diabetes while also showing promise for the prevention and 
treatment of gastrointestinal cancers [3]. However, the absorp-
tion of EGCG is limited, representing only 0.2–2% of the total 
intake in healthy individuals, especially when administered 
orally. Most of it is absorbed in the gastrointestinal system 
and subsequently broken down in the large intestine by 
microorganisms, resulting in a relatively low amount of EGCG 
entering the bloodstream [4,5]. In addition, EGCG exhibits 
instability in neutral and alkaline environments, leading to 
significant degradation in the gastrointestinal tract. This 
instability, along with low membrane permeability and efflux 
mediated by intestinal transporters, results in inefficient 
systemic delivery and low oral bioavailability despite its high 
water solubility. Consequently, researchers have focused on 
developing innovative methods to enhance the stability of 
EGCG and improve its oral bioavailability [6]. Currently, exten-
sive research has been conducted on using various categories 
of nanoparticles such as nanoliposomes [7], solid lipid nano-
particles [8], chitosan nanoparticles [9], and other materials for 
encapsulation and nano-delivery of EGCG. These delivery tech-
nologies have been shown to enhance 1) drug absorption, 2) 
shield drugs from premature degradation, 3) extend drug 
circulation time, 4) demonstrate high selectivity in uptake by 
target cells or tissues over normal cells or tissues, 5) reduce 
toxicity by preventing early interactions with the biological 
environment, 6) enhance intracellular penetration, and more 
particularly in cancer therapy [10–12]. It is important to note 
that high doses of EGCG in extract forms may be harmful, with 
emerging reports on its toxicity. Elevated doses not only cause 
cytotoxicity in vitro but can also lead to hepatotoxicity, and 
gastrointestinal issues such as diarrhea and vomiting. 
Consequently, ongoing research aims to investigate its 
mechanisms and effectiveness to establish EGCG as 
a valuable component in dietary and therapeutic strategies 
[13]. This review summerize the potential of EGCG as 
a versatile therapeutic substance and emphasizes the progress 
in nanotechnology to improve its effectiveness. It aims to 
discuss recent research on the potential effects of EGCG on 
CONTACT Mahdi Adabi madabi@tums.ac.ir Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of 
Medical Sciences, Tehran, Iran; Parisa Sadighara sadighara@farabi.tums.ac.ir Department of Environmental Health Engineering, Division of Food Safety and 
Hygiene, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
NANOMEDICINE 
2025, VOL. 20, NO. 6, 621–636
https://doi.org/10.1080/17435889.2025.2462521
© 2025 Informa UK Limited, trading as Taylor & Francis Group
http://www.tandfonline.com
https://crossmark.crossref.org/dialog/?doi=10.1080/17435889.2025.2462521&domain=pdf&date_stamp=2025-02-20
the mechanisms related to the prevention and treatment of 
metabolic syndrome, with specific attention to hyperlipidemia, 
diabetes, and gastrointestinal (GI) cancers.
2. Enhancement of EGCG-bioavailability through 
nano-formulations
Research indicates that EGCG exhibits greater antioxidant 
activity than vitamin C, resveratrol, and epicatechin [14,15]. 
Additionally, it has shown potential in combating obesity, 
cancer, viral infections, and inflammation, making it 
a promising candidate for medical applications [16,17]. 
Nevertheless, the therapeutic efficacy of EGCG is hindered by 
factors such as the alkaline pH in the intestine, oxidation, and 
low bioavailability [18]. Consequently, efforts are being made 
by researchers to address these limitations. Various studies 
have been undertaken to enhance the bioavailability of 
EGCG through the application of nanotechnology-based stra-
tegies such as liposomes [19], chitosan [20], and polymeric 
nanoparticles [21] as delivery systems. This section discusses 
several types of nanoparticles utilized as carriers for EGCG.
2.1. Nanoparticle-based delivery systems
Numerous research studies have demonstrated that the use of 
nano-carriers for delivering EGCG can improve its stability and 
bioavailability. Different kinds of nanoparticles, including lipid- 
based nanoparticles such as liposomes [22], SLN [23], and NLC 
[24] have been investigated for the encapsulation of EGCG 
(Table 1). For instance, Zou et al [7] developed EGCG nanoli-
posomes using the ethanol injection method in combination 
with dynamic high-pressure microfluidization to enhance the 
in vitro digestion stability of EGCG. Their findings indicated 
a 92% encapsulation efficiency and enhanced stability of 
EGCG in simulated intestinal fluid by the nanoliposomes. In 
another study, a niosomal formulation was employed to 
improve the transport and uptake of EGCG in Caco2 cells. 
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	Abstract
	1. Introduction
	2. Enhancement of EGCG-bioavailability through nano-formulations
	2.1. Nanoparticle-based delivery systems
	3. Hyperlipidemia
	3.1. Cause of hyperlipidemia
	3.2. The effect of EGCG on gut microbiota
	3.3. Effect of EGCG on pancreatic lipase activity
	3.4. The effect of EGCG on HMG-CoA reductaseactivity
	3.5. The effect of EGCG on the AMPK signaling pathway
	4. Diabetes
	4.1. Improvement of insulin sensitivity and enhancement of β-cell function
	4.2.Anti-inflammatory effects of EGCG
	4.3. Reduction of oxidative stress by EGCG
	4.4. Inhibition of hepatic gluconeogenesis by EGCG
	4.5. Clinical trials involving EGCG on type 2 diabetes mellitus and hyperlipidemia
	5. Gastrointestinal (GI) cancers
	5.1. Esophageal cancer
	5.2. GastricCancer
	5.3. Colon cancer
	5.4. Pancreatic cancer
	5.5. Liver cancer
	5.6. Clinical trials involving EGCG on gastrointestinal cancers
	6. Conclusions
	7. Future perspectives
	Acknowledgments
	CRediT authorship contribution statement
	Disclosure statement
	Funding
	Referencesthe utilization of innovative drug delivery systems 
[29]. Moreover, these carriers have the potential to enhance 
targeting ability by modifying their surface characteristics, 
thereby improving cellular uptake and prolonging circulation 
time in the bloodstream [30]. For instance, the upregulation of 
folate receptors (FR) on the surfaces of various cancer cells, 
such as those found in breast, colon, and lung cancers, makes 
them suitable targets for nanoparticle surface modification to 
effectively target cancer cells [30,31]. In a study conducted by 
Farabegoli et al [32] folic acid-functionalized lipid nanoparti-
cles loaded with EGCG were synthesized to specifically target 
breast cancer cells. The findings indicated that targeting can-
cer cells had minimal impact on healthy cells while also exhi-
biting controlled release behavior of EGCG and enhancing its 
bioavailability. In another study, Jia et al [19] developed 
a cyclic RGD (cyclo (Arg-Gly-Asp-D-Phe-Lys))-EGCG liposomal 
delivery carrier to specifically target tumor endothelial cells 
and inhibit thrombosis and vascular inflammation. Their result 
confirmed anti-tumor and anti inflammatory activity of the 
cyclic RGD-EGCG liposomal system and its effectiveness in 
inhibiting thrombosis by specifically targeting tumor endothe-
lial cells.
To fully realize the potential of these advanced drug deliv-
ery systems, it is crucial to understand their in vivo behavior. 
Non-invasive imaging techniques are essential for visualizing, 
quantifying, and monitoring the biodistribution and pharma-
cokinetics of these drug delivery systems over time [33]. 
Imaging plays a crucial role in providing essential data about 
the biodistribution, release process, duration of presence of 
drugs, specificity to the target site [34]. such information is 
important to improve the structure and performance of nano 
based drug delivery systems to enhance their ability to target 
cancer cells and elevate therapeutic efficacy [35–40].
In medical settings, the importance of imaging is magnified 
due to the inherent diversity among individuals and diseases. 
This heterogeneity notably impacts treatment efficacy, parti-
cularly in the application of therapeutic nanomedicines 
[34,41]. Unlike genetically homogeneous animal models, 
human patients present a complex variability both among 
different diseases and within lesions in the same patient. 
This variability has been identified as a major contributor to 
the lower effectiveness of nanomedicines in clinical settings 
compared to their promising results in preclinical trials. 
Therefore, noninvasive imaging methods becomes crucial in 
identifying which patients or specific areas of disease are likely 
to accumulate high levels of nanomedicine. This allows health-
care providers to adjust treatments to individual patient pro-
files, enabling personalized and highly effective nano-based 
therapies [40,42–45]. This integration of advanced imaging not 
only enhances our understanding of drug delivery dynamics 
but also addresses the challenges posed by human heteroge-
neity, leading to more successful clinical outcomes in cancer 
treatment [46]. For example, Yan et al [47] developed mono-
chromatic radiometric imaging nanoparticles (MRIN) technol-
ogy to distinguish distributions of nanoparticles between 
extracellular and intracellular in cancer models. This respon-
sive system used pH and light to activate fluorescence signals, 
enabling precise measurement of nanoparticle localization 
within tumors. Their results showed most of the nanoparticles 
were trapped in extracellular areas, making up 65–80% of total 
tumor exposure, while only 20–35% were found intracellularly. 
By utilizing MRIN technology, they analyzed the impact of 
Article highlights
● EGCG is the primary catechin in green tea.
● EGCG may manage hyperlipidemia by reducing cholesterol 
absorption.
● EGCG enhances insulin sensitivity via the AMPK pathway.
● EGCG inhibits NLRP3 inflammasome, reducing caspase-1 activation.
● Green tea catechins may regulate the cell cycle, combating cancer.
● A nanoplatform could improve EGCG’s treatment efficacy and 
bioavailability.
● Nano drug delivery systems enhance targeting through surface 
modifications.
● Radiolabeling improves tracking of therapeutic agents in 
nanomedicine
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[7
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NANOMEDICINE 623
both extracellular and intracellular distribution of nano- 
photosensitizers on therapeutic effectiveness, thus optimizing 
treatment outcomes. The study employed advanced imaging 
methods to observe and measuredistribution of nanoparticle, 
demonstrating a reliable approach for evaluating in vivo nano-
particle micro-distribution in various types of tumors such as 
pancreatic, colon, and breast cancers. In another study, 
Edmonds et al [48] developed a method for radiolabeling 
liposomal nanomedicines with positron emission tomography 
(PET) radionuclides, facilitating noninvasive imaging and track-
ing of these nanomedicines in vivo. They introduced a simple 
and efficient PET radiolabeling method that utilizes the metal- 
chelating properties of certain drugs, specifically bisphospho-
nates like alendronate and anthracyclines such as doxorubicin. 
These drugs can form stable complexes with PET isotopes 
such as 89Zr, 52Mn, and 64Cu without requiring modifications 
to the nanomedicine components. Their results in preclinical 
models, particularly with metastatic breast cancer, demon-
strated that the radiolabeling technique allowed for effective 
quantification of the biodistribution of radiolabeled stealth 
liposomal nanomedicines. The findings indicated significant 
uptake in primary tumors and provided valuable insights 
into tumor dynamics over time. They suggested that this 
radiolabeling approach could significantly impact the field of 
nanomedicine by enabling better tracking and monitoring of 
therapeutic agents in clinical applications. The ability to radi-
olabel existing formulations without modification opens new 
insight for assessing treatment responses and optimizing.
3. Hyperlipidemia
Hyperlipidemia is a prevalent condition characterized by ele-
vated levels of blood lipids such as cholesterol and triglycer-
ides (TG). Based on studies, dyslipidemia is characterized by 
measurement of the elevated level of TG, fatty free acid (FFA), 
Low-density lipoprotein (LDL), cholesterol, apoB, and reduced 
level of high-density lipoprotein (HDL) [49,50].
3.1. Cause of hyperlipidemia
The American Heart Association (AHA) categorizes hyperlipi-
demia into two groups: primary hyperlipidemia, a genetic 
disorder, and secondary hyperlipidemia, which occurs along-
side conditions such as diabetes, liver, and kidney diseases, 
as well as the use of medications and alcohol [51]. The 
management of hyperlipidemia can be achieved through 
pharmaceutical drugs. However, these medications are asso-
ciated with some side effects. Then, the researcher focused 
on developing a nontoxic safe natural agent to treat or 
reduce the prevalence of hyperlipidemia [52,53]. The poten-
tial benefits of EGCG in managing hyperlipidemia have been 
extensively investigated, and primary findings have been 
documented. However, the exact mechanism of action is 
still not completely founded [54]. This section aims to pro-
vide a brief overview of the anti-hyperlipidemic mechanisms 
of free and nano-encapsulated EGCG.
3.2. The effect of EGCG on gut microbiota
The GI tract is occupied by a large community of microorgan-
isms known as gut microbiota which play various roles in 
regulating the host metabolism such as immune support, 
maintaining the integrity of the intestinal barrier, and regulat-
ing the lipid metabolism. Additionally, gut microbiota modifies 
the structure of bile acids into secondary bile acids. These 
microbial-induced changes have been linked to the incidence 
and progress of hyperlipidemia [55,56].
Tea polyphenols (TPs), as a prebiotic, have the potential effect 
to create optimal conditions to support the growth of beneficial 
microorganisms. These beneficial impacts of TPs may result from 
the ability of gut microbiota to metabolize and utilize specific 
phenolic compounds [57]. EGCG has been found to significantly 
affect the population of gut microbiota in high-fat diet (HFD) 
mice. It increases the abundance of beneficial bacteria such as 
Akkermansia, Adlerceutzia, and Allobactum, while reducing 
harmful bacteria’s populations such as Desulfovibrionaceae. 
This shift in the ratio of gut microbiota population is related to 
host metabolic health, specifically in bile acid metabolism [58]. 
The mechanism of EGCG on gut microbiota has been investi-
gated through its effect on modifying the composition of serum 
bile acid, by increasing the population of specific genera like 
Akkermansia which contribute to the regulation of bile acid 
synthesis and subsequently may improve the dyslipidemia con-
dition [58] as shown in Figure 1. Wen et al [59] evaluated the 
potential effect of TPs and EGCG on hyperlipidemia by modifying 
the gut microbiota community and modulating the liver meta-
bolism. Their results were consistent with the previous studies, 
confirming the effect of TPs on regulating liver metabolism and 
modifying the gut microbiota population. Moreover, these 
changes in the gut microbiota population may lead to changes 
in the metabolic pathway performed by gut microbiota. Then 
Zhou et al [60] evaluated the effect of green tea polyphenols on 
the metabolic pathway in rats over 6 months. Their results con-
firmed the altered metabolic pathway including reduced activ-
ities in the carbohydrate scavenger pathway, bile acid synthesis, 
and absorption of fatty acid. These alterations in the metabolic 
pathway by gut microbiota may have a potential effect on host 
health, particularly in obesity and lipid metabolism.
EGCG exhibits the limited bioavailability due to its chemical 
structure. Therefore, researchers have employed several 
encapsulation methods to improve its bioavailability. Chen 
et al [28] evaluated the effect of oral administration of free 
and nano capsulated EGCG on gut microbiota and hyperlipi-
demia markers in high-fat diet (HFD) rat models. Their finding 
showed that oral administration of EGCG-loaded 
B-cyclodextrin nanoparticles (EGCG@B-CD NPs), compared to 
free EGCG, significantly enhanced the ratio of Verrucomicrobia 
to Bacteroidetes in the intestinal microbiota of rats. Moreover, 
EGCG@B-CD NPs showed the improved efficacy in lowering 
blood lipid levels and protecting the liver compared to free 
EGCG. In another study [61], the effect of (-)-epigallocatechin 
3-O-(3-O-methyl) gallate (EGCG” Me) and EGCG” Me-loaded 
chitosan- casein phosphopeptide (CS-CPP) in intestinal micro-
biota of HFD-induced obesity mice model was investigated. 
The results confirmed the improved proliferative effect of 
EGCG” Me-loaded CS-CPP on beneficial gut bacteria compared 
624 Z. ESMAEILI ET AL.
to free EGCG” Me. Their finding also revealed the enhanced 
bioavailability of EGCG” Me and its potential effect to prevent 
the metabolic syndromes related to obesity.
3.3. Effect of EGCG on pancreatic lipase activity
Pancreatic lipase (PL) plays a essential role in the absorption 
of dietary triacylglycerol by hydrolyzing it into fatty acids 
and monoacylglycerol, increasing its uptake by the body 
[62]. Therefore, many synthetic inhibitors of PL have been 
used to decrease lipolysis products (Figure 1). However, 
they induce the elimination of lipids through fecal exertion, 
leading to significant GI complications and interference 
with the absorption level of fat-soluble vitamins. To address 
this, scientists have focused on discovering novel 
Phospholipase A2 (PLA2) Inhibitors to decrease the side 
effects of synthetic inhibitors [63]. Wu et al [64] character-
ized the binding interaction of EGCG with lipase. Their 
results showed the spontaneous interaction of EGCG and 
lipase through electrostatic force and hydrogen bonds. This 
non-covalent bonding changes the molecular structure of 
lipase, decreasing the enzyme’s catalytic activity. The objec-
tive of this study was to identify a naturally occurring 
inhibitor that could be utilized for the management and 
treatment of both obesity and hyperlipidemia. The oral 
administration of EGCG results in exposure to varying levels 
of acidity, with the stomach registering a pH of 1.5 and the 
primary absorption occurring in the intestine, which has 
a pH of 8.5. Studies [16,65,66] have indicated that the alka-
line condition of the intestinesignificantly limits the bioa-
vailability of EGCG. Therefore, studies focused on improving 
the food-grade encapsulation carriers to enhance the bioa-
vailability and bio-functionality of EGCG. Liang et al [67] 
fabricated the chitosan/zein NPs to protect EGCG from oxi-
dation. Their results showed a controlled release of EGCG, 
which may improve prolonged protection against oxidation. 
In another study [68], dextran sulfate-coated amphiphilic 
chitosan derivative- based on nanoliposomes was used to 
exhibit controlled-release properties and successful protec-
tion of EGCG when exposed to a simulated intestinal 
environment.
3.4. The effect of EGCG on HMG-CoA reductaseactivity
HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reduc-
tase is the main enzyme that regulates the synthesis of 
cholesterol in the liver. Its activity is regulated by sterol 
regulatory element-binding proteins (SREBPs), which are 
transcription factors that specifically regulate genes 
involved in cholesterol production, such as LDL receptors 
and HMG-CoA reductase (Figure 1). Synthetic drugs such as 
statins inhibit HMG-CoA reductase, preventing the conver-
sion of HMG-CoA to mevalonate, the initial step in choles-
terol biosynthesis. This inhibition leads to an increased 
expression of cellular LDL receptors, resulting in higher 
cholesterol uptake from the bloodstream, which further 
lowers plasma cholesterol levels [69]. The effect of green 
tea and its derivative, EGCG, on HMG-CoA reductase has 
been evaluated in several animal studies [70–73]. Zanka 
et al [74] demonstrated that EGCG can up-regulate LDL 
(Low-density lipoprotein) receptors through a 67 kDa lami-
nin receptor-independent pathway in HepG2 cells (a human 
hepatoma cell line). Their findings revealed the potential 
effect of EGCG on LDL receptors through a pathway that is 
independent of the 67 kDa laminin receptor in HepG2 cells. 
In the same study [75], the impact of EGCG on LDL recep-
tors via a decrease in the level of Idol in HepG2 cells was 
investigated. The results revealed that EGCG significantly 
increased the level of LDL protein and reduced the 
increased expression of inducible degrader of the LDLR 
(Idol) and liver X receptor α (LxR α).
Figure 1. The inhibitory effects of EGCG on crucial signaling pathways linked to the regulation of hyperlipidemia.
NANOMEDICINE 625
3.5. The effect of EGCG on the AMPK signaling pathway
AMP-activated protein kinase (5’ adenosine monophosphate- 
activated protein kinase), a serine/threonine kinase, regulates 
energy metabolism in the body. It also plays a crucial role in 
the management of lipid metabolism by controlling malonyl- 
COA synthesis through acetyl COA carboxylase (ACC) [76]. 
Malonyl-COA is an essential precursor in the process of fatty 
acid synthesis. AMPK can inhibit the expression of ACC by 
direct phosphorylation of ACC at serine 2 and serine 79, lead-
ing to the inhibition of fatty acid synthesis and an increase in 
fatty acid oxidation. Therefore, AMPK targeting represents 
a promising therapy for metabolic disorders [77]. Studies [78] 
have shown that EGCG can activate AMPK signaling, which 
regulates lipid metabolism (Figure 1). Wang et al [79] evalu-
ated the effect of EGCG and resveratrol on lipid metabolism in 
hepatocytes through the AMPK pathway. Their finding 
demonstrated that both EGCG and resveratrol activate the 
AMPK pathway, resulting in the inhibition synthesis of choles-
terol in hepatocyte cells. In the same study [80], the role of 
EGCG on lipid, protein, and metabolism of glucose and the 
role of L-Theanine (LTA) in regulating the metabolic effect of 
EGCG were investigated. Their results indicated that EGCG 
stimulates the activation of both the AMPK and insulin path-
way, leading to an increased process of glycogen synthesis, 
glycolysis, and protein synthesis, while simultaneously inhibit-
ing the synthesis of fatty acid and cholesterol. LTA was found 
to improve glycogen metabolism, but it suppressed the effect 
of EGCG on protein and fatty acid synthesis by modulating the 
AMPK signaling pathway.
In conclusion, EGCG demonstrates potential effects in 
managing hyperlipidemia through decreasing cholesterol 
absorption, improving lipid metabolism, and reducing tri-
glycerides (TGA) levels. These results suggest the potential 
use of EGCG as a dietary supplement for people with 
hyperlipidemia. However further research is needed to 
fully comprehend its effect and determine the optimal 
dosage.
4. Diabetes
Diabetes mellitus is a prevalent metabolic disorder on a global 
scale. It can be classified into two primary types based on its 
pathogenesis: type 1 diabetes (T1D), which results from auto-
immune destruction of pancreatic beta cells leading to inade-
quate insulin secretion, and type 2 diabetes (T2D), which is 
primarily caused by insulin resistance and relative insulin defi-
ciency. Both types can lead to hyperglycemia in individuals 
[81]. Studies [82,83] have shown that about 12% of the total 
global healthcare expenses are dedicated to managing dia-
betes, totaling approximately $673 billion. Currently, there is 
no optimal therapy for type 2 diabetes and its long-term 
management, and it is linked with certain adverse effects. 
Medications like insulin and metformin are the primary treat-
ments used in clinical practice for managing both type 1 and 
type 2 diabetes. The utilization of these medications is essen-
tial for managing diabetes, but diabetes itself is linked to 
a significant rise in the likelihood of developing cardiovascular 
disease and encountering mortality from all causes [84]. 
Hence, it is crucial to develop functional foods and nutritional 
medicines that are safe, nontoxic, and economically advanta-
geous as complementary therapies for diabetes management 
EGCG has attracted interest due to its potential advantages in 
the management of type 2 diabetes through various 
mechanisms.
4.1. Improvement of insulin sensitivity and enhancement 
of β-cell function
Insulin resistance, a key characteristic of metabolic disorders, 
plays a significant role in the pathogenesis of both type 2 
diabetes and cardiovascular disease. Based on studies, EGCG 
improves insulin sensitivity by stimulating the AMPK pathway, 
leading to enhanced glucose uptake and metabolism 
(Figure 2). This action contributes to the reduction of insulin 
resistance in tissues such as adipocytes and liver cells [85]. 
A comparative study [86] was carried out to examine how 
Figure 2. A summary of the influence of EGCG on important signaling pathways relevant to diabetes management.
626 Z. ESMAEILI ET AL.
EGCG protects insulin sensitivity in rat L6 muscle cells when 
exposed to dexamethasone. The results showed that dexa-
methasone led to an increase in Ser307 phosphorylation of 
insulin receptor substrate-1 (IRS-1) and a decrease in AMPK 
and Akt phosphorylation. In addition, dexamethasone inhib-
ited uptake of glucose and the translocation of glucose trans-
porter (GLUT4). However, treatment with EGCG led to 
enhanced insulin-stimulated glucose uptake by facilitating 
GLUT4 translocation to the cell membrane. Moreover, the 
study indicated that EGCG effects were mainly dependent on 
the activation of AMPK and Akt. Furthermore, the findings 
suggested that EGCG effectively countered dexamethasone- 
induced insulin resistance through the AMPK and PI3K/Akt 
pathway. In another study [83], male Sprague Dawley rats 
were used to study the effects of EGCG on T2DM induced by 
a high-sucrose high-fat diet and Streptozotocin (STZ) injec-
tions. The rats were given 50 or 100 mg/kg/day of EGCG for 
10 weeks. The results showed that EGCG reduced both fasting 
and postprandial blood glucose levels, enhanced insulin sen-
sitivity, and decreased insulin resistance. Also, it activated 
pancreatic transcription factors, improving β-cell function 
and insulin secretion. Moreover, EGCG enhanced the function-
ality of pancreatic β-cells by upregulating the expression of 
pivotaltranscription factors such as pancreatic and duodenal 
homeobox 1 (PDX-1), which plays a crucial role in insulin 
secretion. This mechanism contributes to the restoration of 
insulin production and secretion in models of diabetes. In the 
same study by Xia et al [87] the impact of EGCG supplementa-
tion on the distribution of pancreatic islet α and β cells in 
adult male mice was investigated. Adult male mice were given 
either 1 or 10 mg/kg/day EGCG through drinking water for 60 
days, and the researchers assessed glucose homeostasis, as 
well as the morphological and molecular changes in the cells. 
The results showed that glucose homeostasis was not affected 
by either dosage of EGCG. The researchers suggested that 
supplementation with EGCG led to a dose-dependent increase 
in β cell mass in adult mice, which in turn affected the levels of 
glucagon and serum insulin. These findings indicated that 
regular tea consumption among individuals without health 
issues might have the potential to prevent diabetes. Zagury 
et al [88] investigated the use of β-Lactoglobulin (β-Lg) as 
a carrier to enhance the biological effectiveness of EGCG in 
a model of HFD mice. Their findings indicated that HFD mice 
treated with EGCG-β-Lg complexes in milk exhibited notably 
decreased levels of liver-triglycerides compared to the control 
group (HFD-water). Additionally, EGCG-β-Lg complexes in milk 
significantly enhanced glucose tolerance in both dietary 
groups compared to free EGCG in milk. Moreover, the entrap-
ment of EGCG in milk by β-Lg appeared to gradually increase 
insulin sensitivity in comparison to free EGCG in milk.
4.2. Anti-inflammatory effects of EGCG
Consumption of an HFD can activate the NOD-like receptor 
protein 3 (NLRP3) inflammasome in macrophages, leading to 
chronic inflammation, immune dysregulation, and insulin 
resistance. The dysregulation of NLRP3 inflammasome is clo-
sely related to the inflammatory response in type 2 diabetes 
and has been well-documented in diabetic patients [89]. 
Researchers suggested that eliminating NLRP3 or inhibiting 
caspase-1 in mice can improve insulin signaling and mitigate 
obesity-related conditions (Figure 2). Therefore, the explora-
tion of small molecule inhibitors targeting the NLRP3 inflam-
masome could be considered an innovative option for 
treatment of diabetes-related diseases [90,91]. Hence, the 
potential effect of EGCG to regulate the activity of NLRP3 
inflammasome activity in vitro was investigated. The 
researchers found that EGCG suppresses the activation of 
caspase-1 and IL-1β secretion by inhibiting NLRP3 inflamma-
some activation in mouse bone marrow-derived macro-
phages (BMDMs). Their results showed that EGCG treatment 
effectively improved glucose tolerance in mice with high-fat 
diet (HFD)-induced type 2 diabetes (T2D) and prevented 
inflammation dependent on NLRP3 inflammasome. 
Moreover, their study illustrated that EGCG could be consid-
ered a general inhibitor of NLRP3 inflammasome activation, 
and administering EGCG to T2D mice improved glucose tol-
erance in in vivo [92]. In another study [93], researchers 
conducted an in vivo assessment of the anti-inflammatory 
properties of EGCG nanophytosome using a rat model. The 
findings showed that EGCG, especially in its nanophytosomal 
form, had a significant effect on reducing inflammation. 
Considering that inflammation is a key factor in many chronic 
conditions (such as neurological disorders, cardiovascular 
diseases, and diabetes), EGCG-loaded nanocarrier may offer 
a hopeful strategy for managing diabetes.
4.3. Reduction of oxidative stress by EGCG
Oxidative stress results from an imbalance between the genera-
tion of reactive oxygen species (ROS) and antioxidants, causing 
disruption in redox signaling and molecular damage. Nonetheless, 
lower levels of ROS can be beneficial and contribute to multiple 
signaling pathways [94]. However, increased levels of ROS asso-
ciated with the incidence of type 2 diabetes, ROS worsen its 
adverse effects by interfering with the regulatory pathways such 
as insulin resistance and β-cell dysfunction, although the specific 
mechanism remains unclear [95]. Dietary antioxidants demon-
strate that anti-diabetic effects also improve diabetic conditions 
by adjusting glucose metabolism, reducing insulin resistance, 
enhancing insulin secretion, and regulating Hemoglobin A1c 
(HbA1c) levels and oxidative stress markers. The antioxidant 
effects of EGCG, investigated in various diseases, reduce oxidative 
stress by neutralizing ROS, a crucial factor contributing to β-cell 
dysfunction and insulin resistance in diabetes [96] (Figure 2). 
Researchers evaluated the effect of EGCG on oxidative stress and 
glucolipid metabolism inT2DM rats. To induce T2DM, the rats were 
fed a high-sucrose high-fat diet and injected with STZ, which led 
to changes in body weight, lipid profile, blood glucose levels, 
insulin resistance, and oxidative stress. Their results showed that 
EGCG effectively enhanced glycemic control and insulin sensitiv-
ity. In addition, it reduced the blood lipid profile and oxidative 
stress in the T2DM rat model [97]. Bulboaca et al [98] showed that 
the liposomal form of EGCG (L-EGCG) reduced oxidative stress 
parameters including malondialdehyde (MDA), indirect nitric 
oxide (NO) synthesis, and total oxidative status (TOS) more effec-
tively than its free form. They suggested that L-EGCG might be 
a promising adjunct treatment for managing diabetes mellitus.
NANOMEDICINE 627
4.4. Inhibition of hepatic gluconeogenesis by EGCG
Glucose is the primary energy source for active tissues like the 
blood cells and brain. Therefore, it’s important to carefully 
regulate its levels in the bloodstream within a specific range 
[99]. The liver plays a vital role in regulating the balance of 
glucose in the body by storing it as glycogen and producing 
glucose through glycogenolysis and gluconeogenesis. Short- 
term fasting causes the liver to release glucose through gly-
cogenolysis, while prolonged fasting results in gluconeogen-
esis, becoming the primary mechanism for regulating blood 
glucose levels. However, increased hepatic gluconeogenesis 
contributes to hyperglycemia in both type 1 and type 2 dia-
betes [100].
Studies have indicated that EGCG can imitate insulin’s 
effects in suppressing hepatic gluconeogenesis. Therefore, it 
may have the potential role to enhance glycemic control. 
Collins et al [101] evaluated the inhibitory effect of EGCG on 
hepatic gluconeogenesis by the AMPK pathway. Their findings 
revealed that EGCG hinders the pathways involved in hepatic 
gluconeogenesis at relatively low concentrations (≤1 μm). This 
mechanism is driven by AMPK activation, which suppresses 
the genes expression associated with gluconeogenesis. In the 
same study, the inhibitory effect of EGCG on hepatic glucose 
production in primary hepatocytes through reduced expres-
sion of the PKA signaling pathway and transcriptional factor 
FoxO1 was investigated. Their findings showed that EGCG 
suppresses gluconeogenesis by antagonizing glucagon signal-
ing and inhibiting FoxO1 at Ser273. As a result, these studies 
proposed that EGCG might be a potential therapeutic 
approach for controlling T2DM [102].
4.5. Clinical trials involving EGCG on type 2 diabetes 
mellitus and hyperlipidemia
Green tea is a popular drink around the world and is believed 
to offer health benefits in the prevention and treatment of 
different illnesses, such as reducing levels of LDL Cholesterol 
(LDL-C). A study (NCT02116517) was conducted to evaluate 
the influence of green tea extract, specificallyEGCG, on lipid 
profiles and other metabolic parameters in obese women with 
high LDL cholesterol levels. This randomized, double-blind, 
placebo-controlled trial involved obese women with high 
LDL cholesterol. It found that the group taking green tea 
extract experienced a notable reduction in LDL-C levels com-
pared to the group taking the placebo. Additionally,improve-
ments were observed in other lipid parameters, such as 
reductions in total cholesterol and triglycerides. The findings 
indicated that green tea extract, particularly EGCG, could be 
a beneficial dietary supplement for managing elevated LDL-C 
levels and enhancing lipid profiles in obese women. These 
results support the potential role of green tea in promoting 
cardiovascular health and metabolic management [103].
Another study (NCT01360567) was carried out to evaluate 
how green tea extract, specifically EGCG, affects lipid profiles 
and glycemic control in people with type 2 diabetes and lipid 
abnormalities. This study involved 92 participants diagnosed 
with type 2 diabetes and hyperlipidemia and was designed as 
a double-blind, randomized, placebo-controlled trial. The 
results suggested that green tea extract could improve insulin 
resistance and positively influence lipid profiles in individuals 
T2DM and hyperlipidemia. Therefore, this research supports 
that the extraction of green tea can be used as 
a complementary approach in managing T2DM and associated 
dyslipidemia [104].
The other study was conducted to assess the effects of 
green tea extract on type 2 diabetes (GTT-DM) 
(NCT00567905). The main purpose of this investigation was 
to examine the impact of green tea extract, specifically EGCG, 
on glycemia and other metabolic factors in people with T2DM. 
The findings indicated improvements in glycemic control in 
participants who were given green tea extract compared to 
those in the placebo group. Notably, there were significant 
decreases in fasting blood glucose and HbA1c levels. 
Moreover, enhancements in insulin sensitivity were observed, 
with a notable reduction in the homeostasis model assess-
ment of insulin resistance (HOMA-IR) index in the green tea 
extract group. In terms of lipid profiles, individuals receiving 
green tea extract showed beneficial changes, including 
decreases in LDL cholesterol and triglycerides. The results 
indicated that green tea extract may be advantageous for 
improving management of glycemia and lipid profiles in indi-
viduals with T2DM. This affirmed the effective role of EGCG as 
a dietary supplement for control of diabetes and associated 
metabolic disorders [105].
5. Gastrointestinal (GI) cancers
GI cancer refers to a range of malignant conditions affecting 
the digestive system, including the esophagus, stomach, liver, 
pancreas, colon, and rectum. In 2018, there were approxi-
mately 4.8 million newly diagnosed cases of GI cancers and 
3.4 million associated deaths reported globally. These types of 
cancers represent 26% of all global cancer incidences and are 
accounted for 35% of cancer-related deaths [106]. Extensive 
efforts have been made to study different treatment options 
for cancer with a particular focus on natural plant compounds 
as potential anti-cancer agents [107]. Studies have revealed 
that green tea catechins can demonstrate anti-cancer effects 
by regulating the cell cycle through the modulation of cyclin- 
dependent kinase (CDK) expression and activation of tumor 
suppressor genes (TSGs), consequently inhibiting growth fac-
tors such as vascular and epidermal factors [108,109]. 
Furthermore, it has been shown that EGCG and green tea 
catechins can induce apoptosis and autophagy by affecting 
various signaling pathways in diverse cellular and animal 
models [110–112], as depicted in Figure 3.
In this section, we briefly discuss the effect of free and 
nano-encapsulated EGCG on GI cancers.
5.1. Esophageal cancer
Esophageal cancer is a frequently identified cancerous condi-
tion affecting the digestive system, particularly prevalent in 
men, and is ranked as the seventh most common cancer and 
sixth in terms of mortality on a global scale. It was reported 
that approximately 572,000 new cases and 509,000 deaths 
occurred worldwide in 2018 [113]. China has the highest 
628 Z. ESMAEILI ET AL.
occurrence of esophageal cancer [114]. Esophageal cancer 
prognosis is typically unfavorable because the majority of 
patients receive a diagnosis at an advanced stage. Although 
there have been advancements in cancer diagnosis and treat-
ment, the mortality rate for esophageal cancer remains high, 
with an average global 5-year survival rate of around 15% to 
25% [115]. The main subtypes of esophageal cancer, esopha-
geal squamous cell carcinoma (ESCC) and esophageal adeno-
carcinoma (EAC) account for over 95% of all malignant 
esophageal tumors [116]. Current treatments for esophageal 
cancer primarily include chemotherapy, surgery, radiotherapy, 
or a combination of these methods, often with significant side 
effects that some patients may find challenging to tolerate. 
Dietary polyphenols have been shown to inhibit the initiation 
and advancement and progression of different forms of can-
cer, such as esophageal cancer [117]. There is a necessary 
requirement for the development of highly effective and low- 
toxicity chemotherapeutic agents for preventing esophageal 
cancer using natural polyphenols. Several studies 
[109,118,119] have suggested that EGCG has the potential to 
increase the sensitivity of cancer cells to radiation therapy and 
has demonstrated its anticancer properties in other research. 
Liu et al conducted a study on the molecular mechanism of 
EGCG in human esophageal squamous cell carcinoma, both 
in vitro and in vivo. The findings revealed that EGCG inhibits 
cell proliferation and triggers cell death by generating ROS, 
activating caspase-3, and reducing vascular endothelial 
growth factor (VEGF) expression, both in vitro and in vivo 
[120]. Zhao et al [121]evaluated the phase I study of EGCG 
for the treatment of ARIE (acute radiation-induced esophagitis) 
induced by radiation. The study results showed that adminis-
tering EGCG orally is a safe, and efficient approach for treating 
ARIE in patients with lung cancer. The encouraging findings 
led to a subsequent prospective assessment of additional 
research studies. Patients with lung cancer and breast cancer 
who were treated with radiation therapy and prescribed EGCG 
had significantly lower RTOG scores compared to the 
untreated control group. These trials confirmed the safety 
and effectiveness of orally administered EGCG for the treat-
ment of ARIE [122–124]. The effectiveness and safety of 
administering EGCG in a phase II clinical trial for the treatment 
of ARIE in patients with esophageal cancer was also investi-
gated. The findings suggested that the oral consumption of 
EGCG seems to be a viable option for managing ARIE in 
individuals undergoing radiation therapy for esophageal can-
cer. EGCG could potentially alleviate ARIE symptoms while 
maintaining the effectiveness of radiation therapy. Finally, 
EGCG might potentially be used in the future for innovative 
treatments aimed at addressing esophageal squamous cell 
carcinoma [125].
5.2. GastricCancer
Gastric cancer is a common type of cancer, ranking as the fifth 
most frequently diagnosed and the third leading cause of 
cancer-related deaths worldwide. The primary treatment for 
patients is gastrectomy. Although, there is significant progress 
in diagnosis and treatment, but the 5 years survival rate fol-
lowing gastrectomy is near 30% [106]. Thus, there is a critical 
need to develop a new strategy for preventing and suppres-
sing the proliferation of gastric cancer cells. The key signaling 
pathways in gastric cancer are Wnt/B catenin, Hedgehog (Hh), 
Hippo, PI3/AKT/mTOR, and Mitogen-Activated Protein Kinases 
(MAPK) signaling pathways [126]. Based on studies, EGCG has 
been shown to inhibit several key signaling pathways which 
involved in to progress of gastric cancer. Yang et al [110] 
evaluated the proliferation rate of the Wnt/B catenin signaling 
Figure 3. The potential EGCE mechanisms on anti-cancer effects. Red arrows (↓) indicate downregulation or suppression, while green arrows (↑) represent 
upregulation or stimulation.
NANOMEDICINE 629
pathway. Theirresults showed that EGCG inhibited the growth 
of SGC-7901 cells and tumor cells in nude mouse xenograft 
models by blocking the activation of the canonical Wnt/b 
catenin signaling pathway. Their finding provides evidence 
that green tea can be utilized as a functional and nutraceutical 
product. Also, the effect of EGCG on the NFK/B signaling 
pathway has been studied. NFK/B is involved in the progres-
sion of tumors through the regulation of genes associated 
with key tumor characteristics including survival, inflamma-
tion, proliferation, and metastasis. EGCG inhibits the NFK/B 
signaling by preventing the effect on phosphorylation and 
therefore degradation of IKBa, which prevents the nuclear 
translocation of p50 and p65 proteins. Additionally, the redu-
cing effect of EGCG on the NFK/B pathway decreased the 
tumor cells’ growth and their invasive potential. The effect of 
EGCG on the PI3K/AKT/mTOR pathway was also investigated. 
PI3K/AKT/mTOR plays an important role in the initiation, 
growth, and progress of cancer, which makes it the potential 
target for cancer treatment [127]. Then, Zhu et al [111] 
assessed the therapeutic impact of EGCG on pre-cancerous 
lesions of gastric carcinoma (PLGC). Their results demonstrated 
that EGCG improved the pathological lesions in PLGC and 
stimulated apoptosis in PLGC rats. The apoptotic pathway 
induced via EGCG may be associated with the suppression of 
the PI3K/AKT/mTOR pathway.
5.3. Colon cancer
Colon cancer, also known as colorectal cancer, is a type of 
cancer that originates in the colon, which is the longest part of 
the large intestine. Major mechanisms of colon cancer devel-
opment are chromosomal instability (CIN), microsatellite 
instability (MSI), and CpG island methylator phenotype 
(CIMP) [128]. CIN is responsible for most colon cancers [129]. 
This pathway often begins with mutations in the APC gene, 
followed by mutations in oncogenes such as Kirsten rat sar-
coma (KRAS) and inactivation of tumor suppressor genes such 
as TP53 [130]. In a study, EGCG significantly reduced the CIN 
and apoptosis rate of normal colon cells (NCM460) at all 
concentrations (5–40 μg/mL) [129]. The reduction of CIN 
causes the cell cycle to stop and allows the cells to repair 
the damaged chromosomes [131]. EGCG ability to reduce CIN 
in normal colon cells is attributed to its antioxidant properties, 
promotion of normal cell division, and reduction of apoptosis 
[132]. EGCG has been shown to stimulate the progression of 
autophagy in different cell types, including cancer cells, and 
provide defense against neurodegenerative diseases. 
Autophagy is a cellular process capable of triggering both 
cell death and cell survival, and it is essential for maintaining 
cellular equilibrium. A research study [133] demonstrated that 
EGCG can modulate the protein levels of death receptors and 
induce autophagic flux in human colon cancer cells.
5.4. Pancreatic cancer
Pancreatic cancer is one of the global problems and it is the 
fourth cause of cancer death in the world [133]. The pancreatic 
cancer pathway involves a series of genetic alterations and com-
plex signaling networks. These signals usually include KRAS, PI3K 
(phosphatidylinositol 3-kinase)/AKT(protein kinase B) pathway, 
TGF(transforming growth factor)-beta signaling [134]. PI3K are 
enzymes involved in cellular functions like growth, proliferation, 
differentiation, and survival. The PI3K pathway is often activated 
in cancer and contributes to tumor growth and survival. AKT is 
a key signaling protein that is activated by PI3K [135]. EGCG 
inhibits the phosphorylation and activation of the PI3K/AKT path-
way, prevents translocation of its factors to the nucleus, and 
promotes apoptosis while inhibiting anti-apoptotic genes [136]. 
It has been shown in various studies that EGCG in relatively low 
doses of 1–40 μM can affect the PI3K/Akt pathway [137]. By 
reducing phosphorylated and total Akt levels, EGCG has been 
shown to successfully inhibit the proliferation of pancreatic can-
cer cells, and enhance the sensitivity of these cells to chemother-
apy, such as gemcitabine. Another possible mechanism of EGCG 
in the prevention of pancreatic cancer is glycolysis suppression. 
Pancreatic cancer cells usually rely on glycolysis to produce 
energy even in the presence of oxygen (Warburg effect) [138]. 
EGCG suppresses glycolysis by inhibiting key glycolytic enzymes, 
including phosphofructokinase and pyruvate kinase. This sup-
pression leads to a decrease in ATP levels and a decrease in the 
rate of extracellular acidification, effectively de-energizing cancer 
cells and promoting apoptosis [139]. Also, Wei et al [140] showed 
that EGCG prevented the “cadherin switch” and decreased the 
expression level of TCF8/ZEB1, vimentin, and β-catenin which 
decreased the proliferation, movement, and penetration of pan-
creatic cancer cells both in vitro and in vivo. Nano-formulations 
can improve the bioavailability, stability, and anti-cancer efficacy 
of EGCG against pancreatic cancer. Two nanoconjugates, EGCG- 
chitosan–gold nanoparticles (EGCG-ChAuNPs) and EGCG- 
cysteamine–AuNPs (EGCG-CystAuNPs), comprising gold nano-
particles, exhibited notable cytotoxic effects on BxPC3 pancreatic 
cancer cells. At EGCG concentrations ranging from 5–10 μM, the 
nanoconjugates reduced BxPC3 cell proliferation to 20–40% 
compared to 87% for free EGCG. The augmented cytotoxicity 
was associated with greater cellular internalization and antiox-
idant potential of nano-EGCG compared to free EGCG [141].
5.5. Liver cancer
Hepatocellular carcinoma (HCC) -primary liver cancer- arises 
from liver cells and is different from secondary liver cancer, 
which originates from other parts of the body and spreads to 
the liver. HCC is characterized by the dysregulation of several 
critical signaling pathways that contribute to its development 
and progression [142]. Key signaling pathways in HCC are 
receptor tyrosine kinases (RTKs), PI3K/AKT/mTOR (mechanistic 
target of rapamycin), RAS (rat sarcoma)/RAF (rapidly acceler-
ated fibrosarcoma)/MEK (mitogen-activated protein kinase)/ 
ERK (extracellular signal-regulated kinase), Wnt(wingless/inte-
grated)/β-catenin, JAK(janus kinase)/STAT(signal transducer 
and activator of transcription), hedgehog (Hh), hippo, TGF-β 
(transforming growth factor-beta) [143].
EGCG exerts its anticancer properties on liver cells by 
affecting different signaling pathways.
(1) By preventing the accumulation of β-catenin in the 
cytoplasm, it prevents its transfer to the nucleus and 
the subsequent activation of Wnt target genes.
630 Z. ESMAEILI ET AL.
(2) EGCG prevents STAT phosphorylation by inhibiting 
Janus kinases (JAK1 and JAK2). This inhibition prevents 
the downstream signaling that promotes tumor growth 
and survival in liver cancer cells.
(3) EGCG prevents the transformation of epithelial cells to 
a more aggressive mesenchymal phenotype by inhibit-
ing the TGF-β pathway, which is involved in epithelial- 
mesenchymal transition (EMT) and cancer metastasis 
[144,145].
In this regard, a study [146] showed that EGCG reduces cell 
death caused by hypoxia and increases cell survival in HepG2 
cells. These results suggest that EGCG can potentially serve as 
an effective treatment for liver cancer. Also, in a rat model of 
diethyl nitrosamine-induced liver injury, clinically achievable 
doses of EGCG (equivalent to a human oral dose of 400 mg 
per day) were well-tolerated and associated with improved 
serum liver markers, reduced HCC tumor formation, and inhi-
bition of fibrosis progression through inactivation of hepatic 
stellate cells and induction of senescence [147]. EGCG concen-
trations of 30 μg/mL can inhibit tumor growth and angiogen-
esis in HCC cells [131]. Additionally, doses of 10 to 20 μM have 
been shown to significantly prevent the invasion capability of 
cancer cells [148]. EGCG-AuNPs show stronger cytotoxic 
effects on liver cancer cells (HepG2) than free EGCG [149]. 
Although otherformulations such as liposomes containing 
EGCG can also increase the bioavailability of EGCG, Au NPs 
provide better stability and cellular uptake [144]. Further com-
parative studies are needed to fully elucidate the advantages 
and potential applications of these various nanoparticle sys-
tems in liver cancer therapy.
5.6. Clinical trials involving EGCG on gastrointestinal 
cancers
Recent developments in clinical trials have focused on the poten-
tial therapeutic effect of EGCG, especially in cancer treatment. 
Several clinical trials are ongoing to evaluate its effectiveness, 
mechanisms of action, and safety in various types of cancer.
A study was carried out to evaluate the preventive effect of 
green tea extracts (GTE) on colorectal adenomas and color-
ectal cancer (NCT02321969). The primary objective of this 
investigation was to assess the preventative impact of GTE 
supplements on metachronous colorectal adenomas by 
administering GTE tablets equivalent to 9 cups of green tea 
per day (0.9 g/day GTE, 0.6 g/day EGCG). The findings indi-
cated that GTE is a beneficial supplement for the chemopre-
vention of metachronous colorectal adenomas, thus 
advocating its potential to decrease the risk of colorectal 
cancer in individuals with a history of adenomatous polyps 
in Korean patients [150]. Another pilot study (NCT02891538) is 
in the process of enrolling patients who have not undergone 
any cancer treatments or, if they are eligible for surgical 
resection, will not receive neoadjuvant chemotherapy. The 
study aims to investigate the chemo-preventive effects of 
EGCG in colorectal cancer patients following curative resection 
and to evaluate DNA methylation changes over the course of 
one year. The investigation is still ongoing, and no publication 
of the findings has been made.
Preclinical research has shown that EGCG is safe and 
effective at preventing hepatocellular carcinoma (HCC). 
Subsequently, a pilot study (NCT06015022) has been started 
to assess the effectiveness of EGCG in preventing hepato-
cellular carcinoma in high-risk patients with underlying liver 
disease or other risk factors. This study is in progress, and 
specific results are not yet to be published. However, based 
on existing literatures on the potential role of EGCG in 
hepatocellular carcinoma (HCC), the background and signif-
icance of the study can be outlined.
6. Conclusions
In conclusion, EGCG exhibits a significant positive impact on 
metabolic disorders and gastrointestinal cancers through 
a variety of mechanisms. It influences lipid metabolism, trig-
gers apoptosis in cancer cells, enhances insulin sensitivity, and 
manages the gut microbiota community. These multifaceted 
actions underscore the potential of EGCG as a therapeutic 
agent for managing metabolic disorders and preventing gas-
trointestinal cancers. However, despite the promising findings, 
further investigation is necessary to fully understand its 
mechanisms, optimize its bioavailability, and confirm its effi-
cacy and safety in clinical settings. Continued research will be 
crucial in translating these preclinical findings into effective 
clinical applications, potentially offering new avenues for the 
treatment and prevention of these prevalent health issues.
7. Future perspectives
A critical aspect of this translation involves the successful 
development of EGCG-loaded nanocarriers. Future studies 
should focus on refining these formulations by optimizing 
their size, surface modifications, encapsulation efficiency, sta-
bility, and targeting capabilities. Additionally, comprehensive 
evaluations of pharmacokinetics and toxicity are vital, along-
side the establishment of scalable manufacturing processes. 
Addressing these challenges will be key to integrating EGCG- 
loaded nanocarriers into the therapeutic landscape for meta-
bolic syndrome and cancer treatment. As the demand for 
novel treatment options continues to grow, these nano- 
based formulations hold significant promise for improving 
patient outcomes and advancing healthcare solutions.
Acknowledgments
During the preparation of this work, the authors used AI (perplexity.ai and 
penelope.ai) in the writing process to improve the readability and lan-
guage of the manuscript. After using this AI, the authors reviewed and 
edited the content as needed and take full responsibility for the content 
of the published article.
CRediT authorship contribution statement
Zahra Esmaeili: Investigation, Conceptualization, Writing – original draft. 
Parisa Shavali Gilani: Investigation, Writing – original draft. Masood 
Khosravani: Visualization. Maral Motamedi: Writing – original draft. 
Shokofeh Maleknejad: Writing – original draft. Mahdi Adabi: 
Supervision, Project administration, Funding acquisition, Writing – review 
& editing. Parisa Sadighara: Investigation, Writing – review & editing.
NANOMEDICINE 631
Disclosure statement
The authors have no relevant affiliations or financial involvement with any 
organization or entity with a financial interest in or financial conflict with 
the subject matter or materials discussed in the manuscript. This includes 
employment, consultancies, honoraria, stock ownership or options, expert 
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Funding
This research was supported by Tehran University of Medical Sciences, 
[Grant No. 1403-3-148-74210].
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